Methods and compositions for treatment of epileptic disorders

ABSTRACT

Use of allosteric modulators and/or gaboxadol for the treatment of epileptic disorders in a subject in need thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/356,517, filed Mar. 18, 2019, which is acontinuation of U.S. patent application Ser. No. 16/013,500, filed Jun.20, 2018, which is a continuation of U.S. patent application Ser. No.15/673,737, filed Aug. 10, 2017, which claims benefit of and priority toU.S. Provisional Application No. 62/490,293, filed Apr. 26, 2017 andU.S. Provisional Application No. 62/373,589, filed Aug. 11, 2016, andwhich are incorporated herein by reference in their respectiveentireties.

TECHNICAL FIELD

Methods of using allosteric modulators and/or gaboxadol orpharmaceutically acceptable salts thereof for the treatment of epilepticdisorders in a subject in need thereof.

BACKGROUND

Allosteric modulators such as neurosteroids (e.g., ganaxolone,allopregnanolone), benzodiazapines (e.g., diazepam) and potassiumchannel openers (e.g., ritigabine) have been used in the treatment ofepilepsy. However, treatment with these agents is often limited topatients that do not respond to traditional medications. For example,allopregnanolone is currently in development for the treatment of superrefractory status epilepticus. In addition, diazepam is currentlymarketed (Diastat®) for use in emergency situations to stop clusterseizures in people who are taking other medications to treat epilepsy.

Gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) (THIP)) isdescribed in EP Patent No. 0000338, in EP Patent No. 0840601, and inU.S. Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005/094820.Gaboxadol is a selective GABA_(A) receptor agonist with a preference forδ-subunit containing GABA_(A) receptors. In the early 1980s gaboxadolwas the subject of a series of pilot studies that tested its efficacy asan analgesic and anxiolytic, as well as a treatment for tardivedyskinesia, Huntington's disease, Alzheimer's disease, and spasticity.In the 1990s gaboxadol moved into late stage development for thetreatment of insomnia but failed to show significant effects in sleeponset and sleep maintenance in a three-month efficacy study.Additionally, patients with a history of drug abuse who receivedgaboxadol experienced a steep increase in psychiatric adverse events. Asa result of these negative results the development of gaboxadol wasterminated.

Parenteral dosage forms are intended for administration as an injectionor infusion. Common injection types are intravenous (into a vein),subcutaneous (under the skin), and intramuscular (into muscle).Infusions typically are given by intravenous route. Parenteralformulations often include excipients to enhance or maintain activeingredient solubility (solubilizers) and/or stability (buffers,antioxidants, chelating agents, cryo- and lyoprotectants). Excipientsalso are important in parenteral formulations to assure safety(antimicrobial preservatives), minimize pain and irritation uponinjection (tonicity agents), and control or prolong drug delivery(polymers). However, excipients may also produce negative effects suchas loss of drug solubility, activity, and/or stability.

There remains a need in the art for safe and effective methods andpharmaceutical compositions that provide epileptic treatment.Accordingly, this disclosure provides pharmaceutical compositions andmethods that may be used in applications of epileptic disorders, such asstatus epilepticus.

SUMMARY

Methods are provided for treatment of epileptic disorders includingepilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy withmyoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy,Landau-Kleffner Syndrome, Ohtahara syndrome, Rasmussen's syndrome,West's syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5disorder, childhood absence epilepsy, essential tremor, Dravet syndrome,Doose syndrome, acute repetitive seizures, benign rolandic epilepsy,status epilepticus, refractory status, epilepticus, super-refractorystatus epilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizureactivity or breakthrough seizures (increased seizure activity, alsocalled serial or cluster seizures) and sodium channel protein type 1subunit alpha (Scn1a)-related disorders by administering to a patient inneed thereof a pharmaceutical composition containing an allostericmodulator. Allosteric modulators include one or more of neurosteroids,benzodiazapines, and potassium channel openers. In embodiments, methodsof treating epileptic disorders are provided which include administeringto a patient in need thereof a pharmaceutical composition including anallosteric modulator in combination with gaboxadol or a pharmaceuticallyacceptable salt thereof.

Parenteral formulations of gaboxadol or pharmaceutically acceptablesalts thereof are provided herein. Methods of treating epilepticdisorders, including status epilepticus, with parenteral formulations ofgaboxadol or a pharmaceutically acceptable salt thereof are provided. Inembodiments, parenteral formulations including gaboxadol or apharmaceutically acceptable salt thereof, alone or in combination withan allosteric modulator, are administered to a patient in need thereofto treat an epileptic disorder.

In embodiments, methods are provided for treatment of epilepticdisorders including status epilepticus, benign rolandic epilepsy (BRE),intractable childhood epilepsy (ICE), childhood absence epilepsy (CAE),juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome),Dravet syndrome and Lennox-Gastaut syndrome (LGS) by administering to apatient in need thereof a pharmaceutical composition including anallosteric modulator either alone or in combination with gaboxadol or apharmaceutically acceptable salt thereof. In embodiments, methods areprovided for treatment of epileptic disorders including statusepilepticus, benign rolandic epilepsy (BRE), intractable childhoodepilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonicepilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome andLennox-Gastaut syndrome (LGS) by administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof either alone or in combinationwith an allosteric modulator.

In embodiments, methods are provided for treatment of epilepticdisorders characterized as a sodium channel protein type 1 subunit alpha(Scn1a)-related disorder. Scn1a-related disorders include generalizedepilepsy with febrile seizures plus, intractable childhood epilepsy withgeneralized tonic-clonic seizures, intractable infantile partialseizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy ininfancy, simple febrile seizures, Dravet syndrome, Lennox-Gastautsyndrome (LGS), infantile spasms, and vaccine-related encephalopathy andseizures. In embodiments, methods are provided for treatment of a sodiumchannel protein type 1 subunit alpha (Scn1a)-related disorder byadministering to a patient in need thereof a pharmaceutical compositionincluding an allosteric modulator. In embodiments, methods are providedfor treatment of a sodium channel protein type 1 subunit alpha(Scn1a)-related disorder by administering to a patient in need thereof apharmaceutical composition including an allosteric modulator incombination with gaboxadol or a pharmaceutically acceptable saltthereof. In embodiments, methods are provided for treatment of a sodiumchannel protein type 1 subunit alpha (Scn1a)-related disorder byadministering to a patient in need thereof a pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereof. Inembodiments, methods are provided for treatment of a sodium channelprotein type 1 subunit alpha (Scn1a)-related disorder by administeringto a patient in need thereof a pharmaceutical composition includinggaboxadol or a pharmaceutically acceptable salt thereof in combinationwith an allosteric modulator. In embodiments, methods are provided fortreatment of a sodium channel protein type 1 subunit alpha(Scn1a)-related disorder by administering to a patient in need thereof aparenteral formulation including gaboxadol or a pharmaceuticallyacceptable salt thereof. In embodiments, methods are provided fortreatment a sodium channel protein type 1 subunit alpha (Scn1a)-relateddisorder by administering to a patient in need thereof a pharmaceuticalcomposition including an allosteric modulator in combination with aparenteral formulation including gaboxadol or a pharmaceuticallyacceptable salt thereof.

In embodiments, a combination of allosteric modulators, e.g., aneurosteroid, benzodiazapine, or potassium channel opener, may beadministered to a patient in need therof. In embodiments, a combinationof one or more allosteric modulators and gaboxadol or a pharmaceuticallyacceptable salt thereof is administered to a patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows both the theoretical and measured solubility of gaboxadolat different pH values.

FIG. 2 is a schematic drawing depicting a timeline for an evaluationstudy of the ability of allopregnanolone, ganaxolone and gaboxadol toblock benzodiazepine resistant status epilepticus in rats.

FIG. 3 is a bar graph depicting the percent protected versus dose withrespect to allopregnanolone, ganaxolone, or gaboxadol.

FIG. 4 is a bar graph depicting the 24-hour survival results based ondose with respect to allopregnanolone, ganaxolone, or gaboxadol.

FIG. 5 is a bar graph showing the number of observed seizures versusdose of allopregnanolone, ganaxolone, or gaboxadol.

FIG. 6A is a bar graph showing body weight changes 24 hours post-statusepilepticus as a function of percent loss versus dose.

FIG. 6B is a bar graph showing 24 hour body weight loss for 0.5 mg/kgdose groups.

FIG. 7 is a schematic drawing depicting a timeline for a prospectiveevaluation study of the ability of allopregnanolone, ganaxolone andgaboxadol to synergistically block benzodiazepine resistant statusepilepticus in rats.

DETAILED DESCRIPTION

Described herein are methods of treating epileptic disorders includingepilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy withmyoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy,Landau-Kleffner Syndrome, Ohtahara syndrome, Rasmussen's syndrome,infantile spasms (or West syndrome), Lennox-Gastaut syndrome (LGS), Rettsyndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder, intractablechildhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenilemyoclonic epilepsy (JME), essential tremor, acute repetitive seizures,benign rolandic epilepsy, status epilepticus, refractory status,epilepticus, super-refractory status epilepticus (SRSE), PCDH19pediatric epilepsy, increased seizure activity or breakthrough seizures(increased seizure activity; also called serial or cluster seizures).Compositions and methods described herein may be used to treat epilepticdisorders characterized as a sodium channel protein type 1 subunit alpha(Scn1A)-related disorder. For example, Scn1A-related disorders includegeneralized epilepsy with febrile seizures, intractable childhoodepilepsy with generalized tonic-clonic seizures, intractable infantilepartial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsyin infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastautsyndrome, infantile spasms, and vaccine-related encephalopathy andseizures. The compositions and methods described herein involveallosteric modulators and/or gaboxadol or a pharmaceutically acceptablesalt thereof.

In embodiments, a method of treating an epileptic disorder may includeadministering to a patient in need thereof a pharmaceutical compositionincluding an allosteric modulator. In embodiments, a method of treatingan epileptic disorder may include administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof. In embodiments, a method oftreating an epileptic disorder may include administering to a patient inneed thereof gaboxadol or a pharmaceutically acceptable salt thereof, incombination with an allosteric modulator. In embodiments, a method oftreating an epileptic disorder may include administering to a patient inneed thereof a parenteral pharmaceutical formulation including anallosteric modulator. In embodiments, a method of treating an epilepticdisorder may include administering to a patient in need thereof aparenteral pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof. In embodiments, a method oftreating an epileptic disorder may include administering to a patient inneed thereof a parenteral pharmaceutical composition including anallosteric modulator and gaboxadol or a pharmaceutically acceptable saltthereof.

Many pharmaceutical products are administered as a fixed dose, atregular intervals, to achieve therapeutic efficacy. The duration ofaction is reflected by the product's plasma half-life. Since efficacy isoften dependent on sufficient exposure within the central nervous systemadministration of CNS drugs with a short half-life may require frequentmaintenance dosing. Advantageously disclosed herein are methods oftreating epileptic disorders by administration of an allostericmodulator. For example, in embodiments, methods of treating an epilepticdisorder are provided which include administering to a patient in needthereof a pharmaceutical composition including about 0.05 mg to about2000 mg of an allosteric modulator wherein the composition providesimprovement for more than 6 hours after administration to the patient.Advantageously disclosed herein are methods of treating epilepticdisorders by administration of gaboxadol or pharmaceutically acceptablesalt thereof. For example, in embodiments, methods of treating anepileptic disorder are provided which include administering to a patientin need thereof a pharmaceutical composition including about 0.05 mg toabout 75 mg of gaboxadol or pharmaceutically acceptable salt thereof,wherein the composition provides improvement for more than 6 hours afteradministration to the patient.

In embodiments, methods of treating an epileptic disorder includeadministering to a patient in need thereof a pharmaceutical compositionincluding about 0.05 mg to about 50 mg gaboxadol or a pharmaceuticallyacceptable salt thereof. In embodiments, methods of treating a epilepticdisorder include administering to a patient in need thereof apharmaceutical composition including about 0.1 mg to about 30 mggaboxadol or a pharmaceutically acceptable salt thereof.

For example, dosages may include amounts of gaboxadol orpharmaceutically acceptable salt thereof in the range of about, e.g.,0.05 mg to 50 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mgto 10 mg, 0.1 mg to 15 mg, 0.1 mg to 30 mg, 0.15 mg to 12.5 mg, or 0.2mg to 10 mg, with doses of 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg,6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15mg, 20 mg, 25 mg, and 30 mg being specific examples of doses.

Typically, dosages of gaboxadol or a pharmaceutically acceptable saltthereof are administered once or twice daily to a patient in needthereof. The methods and compositions described herein may providereduced dosing frequency and reduced adverse events and/or increasedefficacy. In embodiments, the dosage is about, e.g., 0.05-30 mg/day,0.1-20 mg/day, or 0.2-15 mg/day, or 0.5-10 mg/day, or 0.75-5 mg/day, forexample 0.1 mg/day, 0.2 mg/day, 0.5 mg/day, 0.75 mg/day, 1 mg/day, 1.5mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 13 mg/day, 14 mg/day,15 mg/day, 16 mg/day, 17 mg/day, 18 mg/day, 19 mg/day, 20 mg/day, 21mg/day, 22 mg/day, 23 mg/day, 24 mg/day, 25 mg/day, 26 mg/day, 27mg/day, 28 mg/day, 29 mg/day, or 30 mg/day. In embodiments, gaboxadol ora pharmaceutically acceptable salt thereof, or a derivative or analoguethereof is administered at doses of 0.2 mg to 1 mg in infants or 1-20 mgin adults, once daily.

In embodiments, the pharmaceutical compositions include 0.1 mg to 25 mg,0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg,1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg,3 mg to 20 mg, 3 mg to 15 mg gaboxadol or a pharmaceutically acceptablesalt thereof.

In embodiments, the pharmaceutical compositions include 5 mg to 20 mg, 5mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg,12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mggaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, the pharmaceutical compositions include 0.1 mg, 0.25 mg,0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15mg, 17.5 mg, 20 mg gaboxadol or a pharmaceutically acceptable saltthereof or amounts that are multiples of such doses. In embodiments, thepharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg,or 20 mg gaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, the total amount of gaboxadol or pharmaceuticallyacceptable salt thereof and/or gaboxadol administered to a subject in a24-hour period is 1 mg to 50 mg. In embodiments, the total amount ofgaboxadol or pharmaceutically acceptable salt thereof and/or gaboxadoladministered to a subject in a 24-hour period is 1 mg to 20 mg. Inembodiments, the total amount of gaboxadol or pharmaceuticallyacceptable salt thereof and/or gaboxadol administered to a subject in a24-hour period is 5 mg, 10 mg, 15 mg or 20 mg. In embodiments, the totalamount of gaboxadol or a pharmaceutically acceptable salt thereofadministered to a subject in a 24-hour period is 1 mg to 50 mg. Inembodiments, the subject may be started at a low dose and the dosage isescalated. In this manner, it can be determined if the drug is welltolerated in the subject. Dosages can be lower for children than foradults. In embodiments, a dose of gaboxadol for children can be 0.1mg/kg to 1 mg/kg.

Allosteric modulators may include a neurosteroid, e.g., ganaxolone orallopregnanolone, a benzodiazepine, e.g., midazolam, clobazam,clonazepam, diazepam, lorazepam, flurazepam, lorazepam etc., or apotassium channel opener, e.g., retigabine or flupirtine.

In embodiments, methods are provided for treating an epileptic disorderby administering ganaxolone to a patient in need thereof. Inembodiments, methods are provided for treating an epileptic disorder byadministering allopregnanolone to a patient in need thereof. Inembodiments methods are provided for treating an epileptic disorder byadministering a compound of Formula I:

In embodiments, an allosteric modulator or a pharmaceutically acceptablesalt thereof is administered at dosages ranging from about 0.001 mg/kgto about 30 mg/kg of body weight of a patient in need thereof, e.g.,from about 0.01 mg/kg to 20 mg/kg at least once a day. For example,dosages may include amounts of an allosteric modulator or apharmaceutically acceptable salt thereof in the range of about, e.g., 1mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg,0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.1 mg to 10mg, or 0.2 mg to 10 mg, with doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg,0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg,2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg,13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23mg, 24 mg, 25 mg, 26 mg, 27 mg 28 mg, 29 mg, and 30 mg being specificexamples of doses. For example, dosages may include amounts of anallosteric modulator or a pharmaceutically acceptable salt thereof inthe range of about, e.g., 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225mg, 225 mg to 250 mg, 250 mg to 275 mg, 275 mg to 300 mg, 300 mg to 325mg, 325 mg to 350 mg, 350 mg to 375 mg, 375 mg to 400 mg, 400 mg to 425mg, 425 mg to 450 mg, 450 mg to 475 mg, 475 mg to 500 mg, 500 mg to 525mg, 525 mg to 550 mg, 550 mg to 575 mg, 575 mg to 600 mg, 600 mg to 625mg, 625 mg to 650 mg, 650 mg to 675 mg, 675 mg to 700 mg, 700 mg to 725mg, 725 mg to 750 mg, 750 mg to 775 mg, 775 mg to 800 mg, 800 mg to 825mg, 825 mg to 850 mg, 850 mg to 875 mg, 875 mg to 900 mg, 900 mg to 925mg, 925 mg to 950 mg, 950 mg to 975 mg, 975 mg to 1000 mg, 1000 mg to1025 mg, 1025 mg to 1050 mg, 1050 mg to 1075 mg, 1075 mg to 1100 mg,1100 mg to 1125 mg, 1125 mg to 1150 mg, 1150 mg to 1175 mg, 1175 mg to1200 mg, 1200 mg to 1225 mg, 1225 mg to 1250 mg, 1250 mg to 1275 mg,1275 mg to 1300 mg, 1300 mg to 1325 mg, 1325 mg to 1350 mg, 1350 mg to1375 mg, 1375 mg to 1400 mg, 1400 mg to 1425 mg, 1425 mg to 1450 mg,1450 mg to 1475 mg, 1475 mg to 1500 mg, 1500 mg to 1525 mg, 1525 mg to1550 mg, 1550 mg to 1575 mg, 1575 mg to 1600 mg, 1600 mg to 1625 mg,1625 mg to 1650 mg, 1650 mg to 1675 mg, 1675 mg to 1700 mg, 1700 mg to1725 mg, 1725 mg to 1750 mg, 1750 mg to 1775 mg, 1775 mg to 1800 mg,1800 mg to 1825 mg, 1825 mg to 1850 mg, 1850 mg to 1875 mg, 1875 mg to1900 mg, 1900 mg to 1925 mg, 1925 mg to 1950 mg, 1950 mg to 1975 mg, or1975 mg to 2000 mg, of an allosteric modulator.

Typically, dosages of an allosteric modulator or pharmaceuticallyacceptable salts thereof are administered once daily, twice daily, threetimes daily or four times daily to a patient in need thereof. Inembodiments, allosteric modulators may be administered once weekly. Themethods and compositions described herein may provide reduced dosingfrequency and reduced adverse events and/or increased efficacy. Inembodiments, the dosage of an allosteric modulator can be about, e.g.,0.1-20 mg/day, or 0.2-15 mg/day, or 0.5-10 mg/day, or 0.75-5 mg/day, forexample 0.2 mg/day, 0.5 mg/day, 0.75 mg/day, 1 mg/day, 1.5 mg/day, 2mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9mg/day, or 10 mg/day. In embodiments, a patient can be administered anallosteric modulator in an amount of, e.g., 10 mg to 25 mg/day, 25 mg to50 mg/day, 50 mg to 75 mg/day, 75 mg to 100 mg/day, 100 mg to 125mg/day, 125 mg to 150 mg/day, 150 mg to 175 mg/day, 175 mg to 200mg/day, 200 mg to 225 mg/day, 225 mg to 250 mg/day, 250 mg to 275mg/day, 275 mg to 300 mg/day, 300 mg to 325 mg/day, 325 mg to 350mg/day, 350 mg to 375 mg/day, 375 mg to 400 mg/day, 400 mg to 425mg/day, 425 mg to 450 mg/day, 450 mg to 475 mg/day, 475 mg to 500mg/day, 500 mg to 525 mg/day, 525 mg to 550 mg/day, 550 mg to 575mg/day, 575 mg to 600 mg/day, 600 mg to 625 mg/day, 625 mg to 650mg/day, 650 mg to 675 mg/day, 675 mg to 700 mg/day, 700 mg to 725mg/day, 725 mg to 750 mg/day, 750 mg to 775 mg/day, 775 mg to 800mg/day, 800 mg to 825 mg/day, 825 mg to 850 mg/day, 850 mg to 875mg/day, 875 mg to 900 mg/day, 900 mg to 925 mg/day, 925 mg to 950mg/day, 950 mg to 975 mg/day, 975 mg to 1000 mg/day, 1000 mg to 1025mg/day, 1025 mg to 1050 mg/day, 1050 mg to 1075 mg/day, 1075 mg to 1100mg/day, 1100 mg to 1125 mg/day, 1125 mg to 1150 mg/day, 1150 mg to 1175mg/day, 1175 mg to 1200 mg/day, 1200 mg to 1225 mg/day, 1225 mg to 1250mg/day, 1250 mg to 1275 mg/day, 1275 mg to 1300 mg/day, 1300 mg to 1325mg/day, 1325 mg to 1350 mg/day, 1350 mg to 1375 mg/day, 1375 mg to 1400mg/day, 1400 mg to 1425 mg/day, 1425 mg to 1450 mg/day, 1450 mg to 1475mg/day, 1475 mg to 1500 mg/day, 1500 mg to 1525 mg/day, 1525 mg to 1550mg/day, 1550 mg to 1575 mg/day, 1575 mg to 1600 mg/day, 1600 mg to 1625mg/day, 1625 mg to 1650 mg/day, 1650 mg to 1675 mg/day, 1675 mg to 1700mg/day, 1700 mg to 1725 mg/day, 1725 mg to 1750 mg/day, 1750 mg to 1775mg/day, 1775 mg to 1800 mg/day, 1800 mg to 1825 mg/day, 1825 mg to 1850mg/day, 1850 mg to 1875 mg/day, 1875 mg to 1900 mg/day, 1900 mg to 1925mg/day, 1925 mg to 1950 mg/day, 1950 mg to 1975 mg/day, or 1975 mg to2000 mg/day. In embodiments, an allosteric modulator, or a derivative oranalogue thereof can be administered at doses of 0.2 mg to 1 mg ininfants or 1-20 mg in adults, once daily.

In embodiments, a method of treating an epileptic disorder such asstatus epilepticus includes administering ganaxolone or apharmaceutically acceptable salt thereof to a patient in need thereof.Ganaxolone or a pharmaceutically acceptable salt thereof can beadministered in doses ranging from 10 mg/kg to 40 mg/kg, e.g., 11 mg/kgto 39 mg/kg, 12 mg/kg to 38 mg/kg, 13 mg/kg to 37 mg/kg, 14 mg/kg to 36mg/kg, 15 mg/kg to 35 mg/kg, 16 mg/kg to 34 mg/kg, 17 mg/kg to 33 mg/kg,18 mg/kg to 32 mg/kg, 19 mg/kg to 31 mg/kg, 20 mg/kg to 30 mg/kg, 21mg/kg to 29 mg/kg, 22 mg/kg to 28 mg/kg, 23 mg/kg to 27 mg/kg, or 24mg/kg to 26 mg/kg. In embodiments, ganaxolone doses can be, e.g., 50 mg,75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg,300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg,750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg,975 mg, 1000 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg,1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg,1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg,1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg,1975 mg, or 2000 mg.

Ganaxolone or a pharmaceutically acceptable salt thereof can beadministered, e.g., once daily, twice daily, three times daily, or fourtimes daily. In embodiments, ganaxolone or a pharmaceutically acceptablesalt thereof can be administered once weekly. In embodiments, ganaxoloneor a pharmaceutically acceptable salt thereof can be administeredparenterally as soon as possible after the onset of seizures. Inembodiments, ganaxolone or a pharmaceutically acceptable salt thereofcan be administered parenterally in escalating doses as soon as possibleafter the onset of seizures.

In embodiments, a method of treating an epileptic disorder such asstatus epilepticus includes administering allopregnanolone or apharmaceutically acceptable salt thereof to a patient in need thereof.Allopregnanolone or a pharmaceutically acceptable salt thereof can beadministered in doses ranging, e.g., from 0.01 mg/kg to 20 mg/kg, 0.02mg/kg to 19 mg/kg, 0.03 mg/kg to 18 mg/kg, 0.04 mg/kg to 17 mg/kg, 0.05mg/kg to 16 mg/kg, 0.06 mg/kg to 15 mg/kg, 0.07 mg/kg to 14 mg/kg, 0.08mg/kg to 14 mg/kg, 0.09 mg/kg to 13 mg/kg, 0.1 mg/kg to 12 mg/kg, 0.2mg/kg to 11 mg/kg, 0.3 mg/kg to 10 mg/kg, 0.4 mg/kg to 9 mg/kg, 0.5mg/kg to 8 mg/kg, 0.6 mg/kg to 7 mg/kg, 0.7 mg/kg to 6 mg/kg, 0.8 mg/kgto 5 mg/kg, 0.9 mg/kg to 4 mg/kg, or 1 mg/kg to 3 mg/kg. In embodiments,allopregnanolone doses can be, e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg,7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17mg, 18 mg, 19 mg, or 20 mg.

Allopregnanolone or a pharmaceutically acceptable salt thereof can beadministered, e.g., once daily, twice daily, three times daily, or fourtimes daily. In embodiments, allopregnanolone or a pharmaceuticallyacceptable salt thereof can be administered once weekly. In embodiments,allopregnanolone or a pharmaceutically acceptable salt thereof can beadministered parenterally as soon as possible after the onset ofseizures. In embodiments, allopregnanolone or a pharmaceuticallyacceptable salt thereof can be administered parenterally in escalatingdoses as soon as possible after the onset of seizures.

Methods of treating epileptic disorders by administering to a subject inneed thereof an effective amount of gaboxadol or a pharmaceuticallyacceptable salt thereof, either alone or in combination with, anallosteric modulator or a pharmaceutically acceptable salt, derivativeor analogue, or combination thereof, are provided. Methods of treatingepileptic disorders by administering to a subject in need thereof aneffective amount of an allosteric modulator or a pharmaceuticallyacceptable salt, derivative or analogue, or combination thereof, eitheralone or in combination with, gaboxadol or a pharmaceutically acceptablesalt thereof, are provided.

An effective amount or therapeutically effective amount can be a dosagesufficient to treat, inhibit, or alleviate one or more symptoms of anepileptic disorder such as reducing the frequency or severity ofseizures, reducing behavior abnormalities (or otherwise improvingbehavior); or to provide a desired pharmacologic and/or physiologiceffect, for example, reducing, inhibiting, or reversing one or more ofthe underlying pathophysiological mechanisms underlying the neurologicaldysfunction, increasing dopamine levels or signaling, or a combinationthereof. The precise dosage will vary according to a variety of factorssuch as subject-dependent variables (e.g., age, immune system health,clinical symptoms etc.). In embodiments, a subject may be started at alow dose and the dosage is escalated. In this manner, it can bedetermined if the drug is well tolerated in the subject. Dosages can belower for children than for adults.

In embodiments, the methods described herein are effective to reduce,delay, or prevent one or more other clinical symptoms of an epilepticdisorder, such as acute repetitive seizures. For example, the effect ofa gaboxadol or a pharmaceutically acceptable salt thereof, and/or anallosteric modulator or a pharmaceutically acceptable salt, derivativeor analogue thereof, on a particular symptom, pharmacologic, orphysiologic indicator can be compared to an untreated subject, or thecondition of the subject prior to treatment. In embodiments, thesymptom, pharmacologic, and/or physiologic indicator is measured in asubject prior to treatment, and again one or more times after treatmentis initiated. In embodiments, the control is a reference level, oraverage determined based on measuring the symptom, pharmacologic, orphysiologic indicator in one or more subjects that do not have thedisease or condition to be treated (e.g., healthy subjects). Inembodiments, the effect of the treatment is compared to a conventionaltreatment that is known the art.

In embodiments, compositions and methods of treatment are provided withlow dosages of gaboxadol and/or an allosteric modulator such that thepatient is provided one or more beneficial effects related to anepileptic disorder, such as, reduced seizure activity, reduced fatigue,increased mood, increased concentration, increased behavioral controland/or increased cognitive ability. Provided herein are dosing regimensthat allow effective treatment of an epileptic disorder with potentiallylimited or substantially few negative side effects, e.g., convulsionsand/or sleep disruption. Accordingly, the methods described herein mayprovide treatment of an epileptic disorder that may be consideredsurprising and unexpected. For example, methods are provided herein oftreating epileptic disorders in a patient in need thereof which may notcause sleep disruption. In embodiments, methods described herein mayprovide effective treatment of an epileptic disorder withoutinterrupting Slow Wave Sleep. In embodiments, methods of treating anepileptic disorder without causing insomnia or trouble falling asleepare provided.

In embodiments, the methods described herein may be used to treatepileptic disorders including acute repetitive seizures, Landau-KleffnerSyndrome, Lennox-Gastaut syndrome (LGS) and Dravet syndrome. Inembodiments, the methods include treatment of acute repetitive seizure.

In embodiments, the methods described herein may be used to treatepileptic disorders including benign rolandic epilepsy (BRE),intractable childhood epilepsy (ICE), childhood absence epilepsy (CAE),juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome),generalized epilepsy with febrile seizure plus (GEFS+) andLennox-Gastaut syndrome (LGS).

In embodiments, the methods described herein may be used to treat asodium channel protein type 1 subunit alpha (Scn1A)-related disorder.For example Scn1A-related disorders include generalized epilepsy withfebrile seizures plus, intractable childhood epilepsy with generalizedtonic-clonic seizures, intractable infantile partial seizures,myoclonic-astatic epilepsy, severe myoclonic epilepsy in infancy, simplefebrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS),infantile spasms, and vaccine-related encephalopathy and seizures.

The methods described herein may also be effective in subjectsexperiencing intractable seizures, status epilepticus, akineticseizures, myoclonic seizures, absence seizures, or severe myoclonicepilepsy in infancy (SMEI). In embodiments, the disorders arecharacterized by intractable seizures. Intractable seizures (alsoreferred to as “uncontrolled” or “refractory” seizures) are seizuresthat cannot be controlled with conventional treatments. For example, thesubject can have intractable epilepsy or another disorder characterizedby intractable seizures, or a disorder characterized by statusepilepticus. Status epilepticus is a condition in which seizures followone another without recovery of consciousness between them. Accordingly,in embodiments, the disclosed methods are used to treat subjects thatwould otherwise be resistant to one or more conventional therapies.

The methods described herein may be particularly useful for treatingchildren and infants, and for treating disorders that onset duringinfancy or childhood. In embodiments, the subject of the disclosedmethod is a newborn, a baby, a toddler, a preschooler, a school-agechild, a tween, or a teenager. In embodiments, the subject is 18 yearsold or younger, 12 years old or younger, 10 years old or younger, 8years old or younger, 6 years old or younger, 4 years old or younger, 2years old or younger, 1 year old or younger. In embodiments, the subjectis an adult that is over eighteen years old.

In embodiments, the epileptic disorders are characterized by seizuresassociated with epilepsy. In embodiments, the seizures are non-epilepticseizures (NES) or dissociative seizures that are distinguished fromepilepsy. Non-epileptic seizures include organic non-epileptic seizuresand psychogenic seizures.

Epilepsy is a neurological disorder that occurs when nerve cell activityin the brain becomes disrupted, leading to seizures or periods ofunusual behavior, sensations and sometimes loss of consciousness. Asubject can be said to have epilepsy when having two seizures without anobvious cause. Epilepsy can occur in both adults and children, and canbe associated with a specific syndrome. Accordingly, in embodiments, thesubject has a childhood epilepsy syndrome such as benign rolandicepilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonicepilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome orLennox-Gastaut syndrome (LGS).

In embodiments, the subject does not experience diagnosable seizures,but exhibits subclinical electrical discharges, which refers to a highrate of seizure-like activity when their brain waves are measured withan electroencephalogram. Epileptic syndromes associated with theseseizure-like discharges include Landau-Kleffner Syndrome, Dravetsyndrome and Continuous Spike-wave Activity during Slow-wave Sleep.

In embodiments, the epileptic disorders treated by the methods andcompositions described herein include Scn1A-related seizure disorders.Scn1A-related seizure disorders include simple febrile seizures (FS) andgeneralized epilepsy with febrile seizures plus (GEFS+) at the mild endto Dravet syndrome and intractable childhood epilepsy with generalizedtonic-clonic seizures (ICE-GTC) at the severe end. SpecificScn1A-related seizure disorders include, but are not limited to,generalized epilepsy with febrile seizures, intractable childhoodepilepsy with generalized tonic-clonic seizures, intractable infantilepartial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsyin infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastautsyndrome (LGS), infantile spasms, and vaccine-related encephalopathy.

In embodiments, the subject has an intellectual epileptic disability(IDD) such as an Autism Spectrum Disorders (ASD). In embodiments, thesubject of the disclosed method has epilepsy and an IDD or ASD disorder.Common IDD and ASD that are comorbid with seizures and epilepsy include,but are not limited to, fragile X syndrome (FXS), Rett syndrome (RTT),Angelman syndrome, Prader-Willi syndrome, Velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, neuroligin mutations and“interneuronopathies” resulting from aristaless-related homeobox,X-linked (ARX) and Nueropilin 2 (NRP2) gene mutations.

Also provided herein are methods and compositions for treating epilepticdisorders by co-administering to a patient in need thereof an allostericmodulator, and gaboxadol, a derivative thereof, or a pharmaceuticallyacceptable salt thereof. In embodiments, the methods and compositionsdescribed herein include a dosage form including gaboxadol or apharmaceutically acceptable salt thereof, and an allosteric modulator.In embodiments, the methods and compositions described herein caninclude a dosage form including gaboxadol or a pharmaceuticallyacceptable salt thereof, and a separate dosage form including anallosteric modulator or a pharmaceutically acceptable salt thereof.

Gaboxadol or pharmaceutically acceptable salt thereof may be provided asan acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate,hydrochloride or hydrobromide salt, or in the form of the zwitter ionmonohydrate. Acid addition salts, include but are not limited to,maleic, fumaric, benzoic, ascorbic, succinic, oxalic,bis-methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-amino-benzoic, glutamic, benzene sulfonic or theophyllineacetic acid addition salts, as well as the 8-halotheophyllines, forexample 8-bromo-theophylline. In other suitable embodiments, inorganicacid addition salts, including but not limited to, hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric or nitric acid additionsalts may be used.

In embodiments, gaboxadol is provided as gaboxadol monohydrate. Oneskilled in the art will readily understand that the amounts of activeingredient in a pharmaceutical composition will depend on the form ofgaboxadol provided. For example, pharmaceutical compositions ofincluding 5.0, 10.0, or 15.0 mg gaboxadol correspond to 5.6, 11.3, or16.9 mg gaboxadol monohydrate.

In embodiments, gaboxadol is crystalline, such as the crystallinehydrochloric acid salt, the crystalline hydrobromic acid salt, or thecrystalline zwitter ion monohydrate. In embodiments, gaboxadol isprovided as a crystalline monohydrate.

Deuteration of pharmaceuticals to improve pharmacokinetics (PK),pharmacodynamics (PD), and toxicity profiles, has been demonstratedpreviously with some classes of drugs. Accordingly the use of deuteriumenriched gaboxadol is contemplated and within the scope of the methodsand compositions described herein. Deuterium can be incorporated in anyposition in replace of hydrogen synthetically, according to thesynthetic procedures known in the art. For example, deuterium may beincorporated to various positions having an exchangeable proton, such asthe amine N—H, via proton-deuterium equilibrium exchange. Thus,deuterium may be incorporated selectively or non-selectively throughmethods known in the art to provide deuterium enriched gaboxadol. SeeJournal of Labeled Compounds and Radiopharmaceuticals 19(5) 689-702(1982).

Pharmaceutical compositions herein may be provided with immediaterelease, delayed release, extended release, or modified releaseprofiles. In embodiments, pharmaceutical compositions with differentdrug release profiles may be combined to create a two phase orthree-phase release profile. For example, pharmaceutical compositionsmay be provided with an immediate release and an extended releaseprofile. In embodiments, pharmaceutical compositions may be providedwith an extended release and delayed release profile. Such compositionmay be provided as pulsatile formulations, multilayer tablets, orcapsules containing tablets, beads, granules, etc. Compositions may beprepared using a pharmaceutically acceptable “carrier” composed ofmaterials that are considered safe and effective. The “carrier” includesall components present in the pharmaceutical formulation other than theactive ingredient or ingredients. The term “carrier” includes, but isnot limited to, diluents, binders, lubricants, disintegrants, fillers,and coating compositions.

In embodiments, the pharmaceutical compositions described herein areadministered once, twice, three times or four times daily, or everyother day. In embodiments, a pharmaceutical composition described hereinis provided to the patient in the evening. In embodiments, apharmaceutical composition described herein is provided to the patientonce in the evening and once in the morning. In embodiments, apharmaceutical composition herein is provided as soon as possible afterthe occurrence of a seizure. In embodiments, a pharmaceuticalcomposition herein is provided continuously.

In embodiments, the total amount of allosteric modulator and/orgaboxadol administered to a subject in a 24-hour period is 1 mg to 50mg. In embodiments, the total amount of allosteric modulator and/orgaboxadol administered to a subject in a 24-hour period is 1 mg to 20mg. In embodiments, the total amount of allosteric modulator and/orgaboxadol administered to a subject in a 24-hour period is 5 mg, 10 mg,or 15 mg. In embodiments, the total amount of allosteric modulatorand/or gaboxadol or a pharmaceutically acceptable salt thereofadministered to a subject in a 24-hour period is 1 mg to 50 mg. Inembodiments, the subject may be started at a low dose and the dosage isescalated. In this manner, it can be determined if the drug is welltolerated in the subject. Dosages can be lower for children than foradults.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof apharmaceutical composition including an allosteric modulator and/orgaboxadol wherein the composition provides improvement in at least onesymptom of the epileptic disorder. In embodiments, methods of treatingepileptic disorders by administering to a subject in need thereof aneffective amount of allosteric modulator and/or gaboxadol, orcombination thereof, are provided. An effective amount ortherapeutically effective amount can be a dosage sufficient to treat,inhibit, or alleviate one or more symptoms of an epileptic disorder suchas reducing the frequency or severity of seizures, reducing behaviorabnormalities (or otherwise improving behavior); or to provide a desiredpharmacologic and/or physiologic effect, for example, reducing,inhibiting, or reversing one or more of the underlyingpathophysiological mechanisms underlying the neurological dysfunction,increasing dopamine levels or signaling, or a combination thereof. Theprecise dosage will vary according to a variety of factors such assubject-dependent variables (e.g., age, immune system health, clinicalsymptoms etc.).

In embodiments, the methods described herein are effective to reduce,delay, or prevent one or more other clinical symptoms of an epilepticdisorder, e.g., epilepsy or Dravet syndrome. For example, the effect ofa composition including allosteric modulator and/or gaboxadol on aparticular symptom, pharmacologic, or physiologic indicator can becompared to an untreated subject, or the condition of the subject priorto treatment. In embodiments, the symptom, pharmacologic, and/orphysiologic indicator is measured in a subject prior to treatment, andagain one or more times after treatment is initiated. In embodiments,the control is a reference level, or average determined based onmeasuring the symptom, pharmacologic, or physiologic indicator in one ormore subjects that do not have the disease or condition to be treated(e.g., healthy subjects). In embodiments, the effect of the treatment iscompared to a conventional treatment that is known the art.

In embodiments, provided herein are methods of treating an epilepticdisorder, e.g., status epilepticus, including administering to a patientin need thereof a pharmaceutical composition including an allostericmodulator and/or gaboxadol or pharmaceutically acceptable salt thereofwherein the composition provides improvement in at least one symptom ofthe epileptic disorder. In embodiments, the methods provided may alsosurprisingly and unexpectedly reduce or prevent seizures, or symptomsthereof in a subject in need thereof. In embodiments, the methodsprovided may reduce or prevent one or more different types of seizures.In embodiments, the methods provided may also surprisingly andunexpectedly reduce or prevent seizures, or symptoms thereof in asubject in need thereof. In embodiments, the methods provided may reduceor prevent one or more different types of seizures. Generally, a seizurecan include convulsions, repetitive movements, unusual sensations, andcombinations thereof. Seizures can be categorized as focal seizures(also referred to as partial seizures) and generalized seizures. Focalseizures affect only one side of the brain, while generalized seizuresaffect both sides of the brain. Specific types of focal seizures includesimple focal seizures, complex focal seizures, and secondarilygeneralized seizures. Simple focal seizures can be restricted or focusedon a particular lobe (e.g., temporal lobe, frontal lobe, parietal lobe,or occipital lobe). Complex focal seizures generally affect a largerpart of one hemisphere than simple focal seizures, but commonlyoriginate in the temporal lobe or the frontal lobe. When a focal seizurespreads from one side (hemisphere) to both sides of the brain, theseizure is referred to as a secondarily generalized seizure. Specifictypes of generalized seizures include absences (also referred to aspetit mal seizures), tonic seizures, atonic seizures, myoclonicseizures, tonic clonic seizures (also referred to as grand malseizures), and clonic seizures.

In embodiments, methods described herein may reduce the frequency ofseizures, reduce the severity of seizures, change the type of seizures(e.g., from a more severe type to a less severe type), or a combinationthereof in a subject after treatment compared to the absence oftreatment (e.g., before treatment), or compared to treatment with analternative conventional treatment.

In embodiments, provided herein are methods of treating an epilepticdisorder wherein the patient is provided improvement of at least onesymptom for more than 4 hours after administration of the pharmaceuticalcomposition to the patient. In embodiments, the improvement of at leastone symptom for more than 6 hours after administration of thepharmaceutical composition to the patient is provided in accordance withthe present disclosure. In embodiments, improvement of at least onesymptom for more than, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18hours, 20 hours, or 24 hours after administration of the pharmaceuticalcomposition to the patient is provided in accordance with the presentdisclosure. In embodiments, improvement in at least one symptom for atleast e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours,or 24 hours after administration of the pharmaceutical composition tothe patient is provided in accordance with the present disclosure. Inembodiments, improvement in at least one symptom for 12 hours afteradministration of the pharmaceutical composition to the patient isprovided in accordance with the present disclosure.

In embodiments, provided herein methods of treating an epilepticdisorder including administering a composition herein to a patient inneed thereof wherein the composition provides improvement in next dayfunctioning to the patient.

In embodiments, provided herein are methods of treating an epilepticdisorder wherein the amount of active substance, e.g., allostericmodulator and/or gaboxadol, within the patient about 4 hours afteradministration of the pharmaceutical composition is less than about 75%of the administered dose. In embodiments, provided herein are methodswherein the amount of allosteric modulator and/or gaboxadol orpharmaceutically acceptable salt thereof within the patient about, e.g.,6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours afteradministration of the pharmaceutical composition is less than about 75%.

In embodiments, provided herein are methods of treating an epilepticdisorder wherein the amount of active substance, e.g., allostericmodulator and/or gaboxadol, within the patient about 4 hours afteradministration of the pharmaceutical composition is less than about 80%of the administered dose. In embodiments, provided herein are methodswherein the amount of active substance, e.g., allosteric modulatorand/or gaboxadol, within the patient about, e.g., 6 hours, 8 hours, 10hours, 12 hours, 15 hours, or 20 hours after administration of thepharmaceutical composition is less than about 80% of the administereddose.

In embodiments, provided herein are methods of treating an epilepticdisorder wherein the amount of active substance, e.g., allostericmodulator and/or gaboxadol, within the patient about 4 hours afteradministration of the pharmaceutical composition is between about 65% toabout 85% of the administered dose. In embodiments, the amount of activesubstance, e.g., allosteric modulator and/or gaboxadol, within thepatient after about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15hours, or 20 hours after administration of the pharmaceuticalcomposition is between about 65% to about 85% of the administered dose.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof apharmaceutical composition including an active substance, e.g.,allosteric modulator and/or gaboxadol, wherein the composition providesan in vivo plasma profile having a C_(max) less than about 500 ng/ml. Inembodiments, the composition provides improvement for more than 6 hoursafter administration to the patient.

In embodiments, the composition provides an in vivo plasma profilehaving a C_(max) less than about, e.g., 450 ng/ml, 400 ng/ml 350 ng/ml,or 300 ng/ml and wherein the composition provides improvement of nextday functioning of the patient. In embodiments, the composition providesan in vivo plasma profile having a C_(max) less than about, e.g., 250ng/ml, 200 ng/ml 150 ng/ml, or 100 ng/ml and wherein the compositionprovides improvement of next day functioning of the patient.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof apharmaceutical composition wherein the composition provides a consistentin vivo plasma profile having a AUC_(0-∞) of less than about 900ng·hr/ml. In embodiments, the composition provides improvement in nextday functioning of the patient. In embodiments, the compositions providean in vivo plasma profile having a AUC_(0-∞) of less than about, e.g.,850 ng·hr/ml, 800 ng·hr/ml, 750 ng·hr/ml, or 700 ng·hr/ml and whereinthe composition provides improvement of next day functioning of thepatient. In embodiments, the composition provides improvement in one ormore symptom for more than 6 hours after administration.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof apharmaceutical composition including an active substance, e.g.,allosteric modulator and/or gaboxadol, wherein the composition providesan in vivo plasma profile having a AUC_(0-∞) of less than about, e.g.,650 ng·hr/ml, 600 ng·hr/ml, 550 ng·hr/ml, 500 ng·hr/ml, or 450 ng·hr/ml.In embodiments, wherein the composition provides an in vivo plasmaprofile having a AUC_(0-∞) of less than about, e.g., 400 ng·hr/ml, 350ng·hr/ml, 300 ng·hr/ml, 250 ng·hr/ml, or 200 ng·hr/ml. In embodiments,the composition provides an in vivo plasma profile having a AUC_(0-∞) ofless than about, e.g., 150 ng·hr/ml, 100 ng·hr/ml, 75 ng·hr/ml, or 50ng·hr/ml. In embodiments, the composition provides improvement of nextday functioning of the patient after administration for more than, e.g.,4 hours, 6 hours, 8 hours, 10 hours, or 12 hours, after administrationof the composition to the patient.

In embodiments, provided herein are methods of treating a epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical composition including gaboxadol or a pharmaceuticallyacceptable salt thereof and a second pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereof. Insome embodiments, the second pharmaceutical composition provides an invivo plasma profile having a mean AUC_(0-∞) of at least about 20% lessthan the first pharmaceutical composition.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical composition including an allosteric modulator and asecond pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof. In embodiments, the secondpharmaceutical composition provides an in vivo plasma profile having amean AUC_(0-∞) of at least about 20% less than the first pharmaceuticalcomposition.

In embodiments, the first and/or the second pharmaceutical compositionsare administered once, twice, three or four times daily, or every otherday. In embodiments, the first or the second pharmaceutical compositionis provided to the patient in the evening. In embodiments, the secondpharmaceutical composition includes an amount of gaboxadol that is atleast one third of the amount of the allosteric modulator in the firstpharmaceutical composition. In embodiments, the second pharmaceuticalcomposition includes an amount of gaboxadol that is at least half of theamount of the amount of the allosteric modulator provided in the firstpharmaceutical composition.

In embodiments, the first and/or the second pharmaceutical compositionare provided to the patient once in the evening and once in the morning.In embodiments, the total amount of allosteric modulator administered toa subject in a 24-hour period is 1 mg to 2500 mg. In embodiments, thetotal amount of allosteric modulator administered to a subject in a24-hour period is 1 mg/kg to 35 mg/kg. In embodiments, the total amountof gaboxadol or a pharmaceutically acceptable salt thereof administeredto a subject in a 24-hour period is 1 mg to 75 mg. In embodiments, thetotal amount of active substance, e.g., gaboxadol or pharmaceuticallyacceptable salt thereof, administered to a subject in a 24-hour periodis less than about 75 mg, 50 mg, 25 mg, 20 mg, 10 mg, or 5 mg. Inembodiments, the total amount of active substance, e.g., gaboxadol orpharmaceutically acceptable salt thereof, administered to a subject in a24-hour period is less than 15 mg. In embodiments, the total amount ofactive substance, e.g., allosteric modulator and/or gaboxadol,administered to a subject in a 24-hour period is less than about 2500mg, 2250 mg, 2000 mg, 1750 mg, 1500 mg, 1250 mg, 1000 mg, 750 mg, 500mg, 250 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 75 mg, 50 mg, 25 mg,20 mg, 10 mg, or 5 mg. In embodiments, the total amount of activesubstance, e.g., allosteric modulator and/or gaboxadol, administered toa subject in a 24-hour period is less than 15 mg.

In embodiments, the first and/or the second pharmaceutical compositionsmay be provided with immediate release, delayed release, extendedrelease, or modified release profiles. The first and secondpharmaceutical compositions may be provided at the same time orseparated by an interval of time, e.g., 6 hours, 12 hours etc. Inembodiments, the first and the second pharmaceutical compositions may beprovided with different drug release profiles to create a two-phaserelease profile. For example, the first pharmaceutical composition maybe provided with an immediate release profile and the secondpharmaceutical composition may provide an extended release profile. Inembodiments, one or both of the first and second pharmaceuticalcompositions may be provided with an extended release or delayed releaseprofile. Such compositions may be provided as pulsatile formulations,multilayer tablets or capsules containing tablets, beads, granules, etc.In some embodiments, the first pharmaceutical composition is animmediate release composition. In embodiments, the second pharmaceuticalcomposition is an immediate release composition. In embodiments, thefirst and second pharmaceutical compositions are provided as separateimmediate release compositions, e.g., tablets or capsules. Inembodiments the first and second pharmaceutical compositions areprovided 12 hours apart.

In embodiments, compositions described herein are suitable forparenteral administration, including, e.g., intramuscularly (i.m.),intravenously (i.v.), subcutaneously (s.c.), intraperitoneally (i.p.),or intrathecally (i.t.). Parenteral compositions must be sterile foradministration by injection, infusion or implantation into the body andmay be packaged in either single-dose or multi-dose containers.

In embodiments, liquid pharmaceutical compositions for parenteraladministration to a subject include an active substance, e.g.,allosteric modulator and/or gaboxadol, at a concentration of about 0.005μg/ml to about 500 μg/ml. In embodiments, the composition comprises anactive substance, e.g., allosteric modulator and/or gaboxadol, at aconcentration of, e.g., about 0.005 μg/ml to about 250 μg/ml, about0.005 μg/ml to about 200 μg/ml, about 0.005 μg/ml to about 150 μg/ml,about 0.005 μg/ml to about 100 μg/ml, or about 0.005 μg/ml to about 50μg/ml.

In embodiments, the compositions comprises an active substance, e.g.,allosteric modulator and/or gaboxadol, at a concentration of, e.g.,about 0.05 μg/ml to about 50 μg/ml, about 0.1 μg/ml to about 50 μg/ml,about 0.05 μg/ml to about 25 μg/ml, about 0.05 μg/ml to about 10 μg/ml,about 0.05 μg/ml to about 5 μg/ml, or about 0.05 μg/ml to about 1 μg/ml.In embodiments, the composition comprises an active substance, e.g.,allosteric modulator and/or gaboxadol, at a concentration of, e.g.,about 0.05 μg/ml to about 15 μg/ml, about 0.5 μg/ml to about 10 μg/ml,about 0.5 μg/ml to about 7 μg/ml, about 1 μg/ml to about 10 μg/ml, about5 μg/ml to about 10 μg/ml, or about 5 μg/ml to about 15 μg/ml. Inembodiments, the pharmaceutical compositions for parenteraladministration is formulated as a total volume of about, e.g., 10 ml, 20ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, thecompositions are contained in a bag, a glass vial, a plastic vial, or abottle.

In embodiments, compositions for parenteral administration include about0.05 mg to about 100 mg active substance, e.g., allosteric modulatorand/or gaboxadol. In embodiments, the pharmaceutical compositionscomprise about, e.g., 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg,0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg,2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mgactive substance, e.g., allosteric modulator and/or gaboxadol.

In embodiments, pharmaceutical compositions include about, e.g., 5 mg to20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mgto 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20mg active substance, e.g., allosteric modulator and/or gaboxadol. Inembodiments, the pharmaceutical compositions include about, e.g., 0.1mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg active substance, e.g., allostericmodulator and/or gaboxadol, or amounts that are multiples of such doses.The compositions may be contained in a bag, a glass vial, a plasticvial, or a bottle.

In embodiments, pharmaceutical compositions for parenteraladministration to a subject include an active substance, e.g.,allosteric modulator and/or gaboxadol, at a concentration of about 0.005mg/ml to about 500 mg/ml. In embodiments, the compositions include anactive substance, e.g., allosteric modulator and/or gaboxadol, at aconcentration of, e.g., about 0.05 mg/ml to about 50 mg/ml, about 0.1mg/ml to about 50 mg/ml, about 0.1 mg/ml to about 10 mg/ml, about 0.05mg/ml to about 25 mg/ml, about 0.05 mg/ml to about 10 mg/ml, about 0.05mg/ml to about 5 mg/ml, or about 0.05 mg/ml to about 1 mg/ml. Inembodiments, the composition includes an active substance, e.g.,allosteric modulator and/or gaboxadol, at a concentration of, e.g.,about 0.05 mg/ml to about 15 mg/ml, about 0.5 mg/ml to about 10 mg/ml,about 0.25 mg/ml to about 5 mg/ml, about 0.5 mg/ml to about 7 mg/ml,about 1 mg/ml to about 10 mg/ml, about 5 mg/ml to about 10 mg/ml, orabout 5 mg/ml to about 15 mg/ml. In embodiments, pharmaceuticalcompositions for parenteral administration are formulated as a totalvolume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250ml, or 500 ml. In embodiments, the compositions are packages and storedin a bag, a glass vial, a plastic vial, or a bottle.

In embodiments, pharmaceutical compositions herein include an activesubstance, e.g., allosteric modulator and/or gaboxadol, wherein theactive substance is present at a molarity less than about 1.0 M. Inembodiments, the active substance, e.g., allosteric modulator and/orgaboxadol, is present at a molarity greater than, e.g., about 0.0001 Mabout 0.001 M, about 0.01 M, about 0.1 M, about 0.2 M, greater thanabout 0.5, greater than about 1.0 M, greater than about 1.2 M, greaterthan about 1.5 M, greater than about 1.75 M, greater than about 2.0 M,or greater than about 2.5 M. In embodiments, the active substance, e.g.,allosteric modulator and/or gaboxadol, is present at a molarity ofbetween, e.g., about 0.00001 M to about 0.1 M, about 0.01 to about 0.1M, about 0.1 M to about 1.0 M, about 1.0 M to about 5.0 M, or about 5.0M to about 10.0 M. In embodiments, the active substance, e.g.,allosteric modulator and/or gaboxadol, is present at a molarity of lessthan, e.g., about 0.01 M, about 0.1 M, about 1.0 M, about 5.0 M, orabout 10.0 M.

In embodiments, the solubility of the active substance, e.g., allostericmodulator and/or gaboxadol, in the composition is greater than, e.g.,about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30mg/mL, about 40 mg/mL, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL,about 150 mg/mL, when measured, for example, in water at 25° C.

In embodiments, the solubility of the active substance, e.g., allostericmodulator and/or gaboxadol, in the composition is between, e.g., about 1mg/mL to about 50 mg/mL, about 5 mg/mL to about 50 mg/mL, about 10 mg/mLto about 50 mg/mL, about 20 mg/mL to about 50 mg/ml, from about 20 mg/mLto about 30 mg/mL or from about 10 mg/mL to about 45 mg/mL, whenmeasured, for example, in water at 25 C.

In embodiments, a pharmaceutical composition for parenteraladministration is provided wherein the pharmaceutical composition isstable for at least six months. In embodiments, the pharmaceuticalcompositions herein exhibit no more than about 5% decrease in activesubstance, e.g., allosteric modulator and/or gaboxadol, e.g., 3 monthsor 6 months. In embodiments, the amount of gaboxadol or pharmaceuticallyacceptable salt thereof degrades at no more than about, e.g., 2.5%, 1%,0.5% or 0.1%. In embodiments, the degradation is less than about, e.g.,5%, 2.5%, 1%, 0.5%, 0.25%, 0.1%, for at least six months.

In embodiments, pharmaceutical compositions for parenteraladministration are provided wherein the pharmaceutical compositionremains soluble. In embodiments, pharmaceutical compositions areprovided that are stable, soluble, local site compatible and/orready-to-use. In embodiments, the pharmaceutical compositions herein areready-to-use for direct administration to a patient in need thereof.

The parenteral compositions provided herein may comprise one or moreexcipients, e.g., solvents, solubility enhancers, suspending agents,buffering agents, isotonicity agents, stabilizers or antimicrobialpreservatives. When used, the excipients of the parenteral compositionswill not adversely affect the stability, bioavailability, safety, and/orefficacy of allosteric modulator and/or gaboxadol or pharmaceuticallyacceptable salt(s) used in the composition. Thus, parenteralcompositions are provided wherein there is no incompatibility betweenany of the components of the dosage form.

In embodiments, parenteral compositions of allosteric modulator and/orgaboxadol or a pharmaceutically acceptable salt thereof include astabilizing amount of at least one excipient. For example, excipientsmay be selected from the group consisting of buffering agents,solubilizing agents, tonicity agents, antioxidants, chelating agents,antimicrobial agents, and preservative. One skilled in the art willappreciate that an excipient may have more than one function and beclassified in one or more defined group.

In embodiments, pharmaceutical compositions include an allostericmodulator and/or gaboxadol, or a pharmaceutically acceptable saltthereof and an excipient wherein the excipient is present at a weightpercent (w/v) of less than about, e.g., 10%, 5%, 2.5%, 1%, or 0.5%. Inembodiments, the excipient is present at a weight percent between about,e.g., 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%,0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. In embodiments, the excipient ispresent at a weight percent between about, e.g., 0.001% to 1%, 0.01% to1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.

In embodiments pharmaceutical compositions are provided includinggaboxadol, or a pharmaceutically acceptable salt thereof, and anexcipient wherein the excipient is present in a molar ratio of theexcipient to gaboxadol or pharmaceutically acceptable salt of, e.g.,about 0.01:1 to about 0.45:1, about 0.1:1 to about 0.15:1, about 0.01:1to about 0.1:1, and about 0.001:1 to about 0.01:1 are provided. Inembodiments, the excipient is present at a molar ratio of the excipientto gaboxadol or pharmaceutically acceptable salt is about 0.0001:1 toabout 0.1:1 or about 0.001:1 to about 0.001:1.

In embodiments, pharmaceutical compositions are provided includinggaboxadol, or a pharmaceutically acceptable salt thereof and anexcipient wherein the excipient comprises a stabilizing amount of abuffering agent. The buffering agent may be used to maintain the pH ofthe pharmaceutical composition wherein the gaboxadol or pharmaceuticallyacceptable salt thereof remains soluble, stable, and/or physiologicallycompatible. For example, in embodiments, the parenteral compositionsinclude a buffering agent wherein the composition remains stable withoutsignificant gaboxadol degradation. In embodiments, the addition of abuffer is desired for controlling the pH to enhance stability withoutsignificantly catalyzing or degrading the gaboxadol or salt thereofand/or causing pain to the patient upon infusion.

In embodiments, the buffering agent can be a citrate, phosphate,acetate, tartrate, carbonate, glutamate, lactate, succinate, bicarbonatebuffer and combinations thereof. For example, sodium citrate, trisodiumcitrate anhydrous, trisodium citrate dihydrate, sodium citratedehydrate, triethanolamine (TRIS), trisodium citrate pentahydratedihydrate (i.e., trisodium citrate dehydrate), acetic acid, citric acid,glutamic acid, phosphoric acid, may be used as a buffering agent. Inembodiments, the buffering agent may be an amino acid, alkali metal, oralkaline earth metal buffer. For example, the buffering agent may besodium acetate or hydrogen phosphate.

In embodiments, parenteral compositions of an active substance, e.g.,allosteric modulator and/or gaboxadol are provided, wherein the pH ofthe composition is between about 4.0 to about 8.0. In embodiments, thepH of the compositions is between, e.g., about 5.0 to about 8.0, about6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pH of thecompositions is between, e.g., about 6.5 to about 7.5, about 7.0 toabout 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. Inembodiments, the pH of the aqueous solution is, e.g., about 6.8, about7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0,about 8.2, about 8.4, or about 8.6.

In embodiments, pharmaceutical compositions of an active substance,e.g., allosteric modulator and/or gaboxadol, or a pharmaceuticallyacceptable salt thereof, and an excipient wherein the excipient includesa solubilizing agent. For example, solubilizing agents according to theinvention may include, e.g., sodium hydroxide, L-lysine, L-arginine,sodium carbonate, potassium carbonate, sodium phosphate, and/orpotassium phosphate. The amount of solubilizing agent in the compositionwill be sufficient such that the solution remains soluble at allconcentrations, i.e., does not turn hazy and/or form precipitates.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes a particulate formation inhibitor. A particulateformation inhibitor refers to a compound that has the desired propertyof inhibiting the formation of particles in parenteral compositions.Particulate formation inhibitors of the invention includeethylenediaminetetraacetic acid (EDTA) and salts thereof, for example,ethylenediaminetetraacetic acid, calcium disodium salt (preferably asthe hydrate); ethylenediaminetetraacetic acid, diammonium salt(preferably as the hydrate); ethylenediaminetetraacetic acid,dipotassium salt (preferably as the dihydrate);ethylenediaminetetraacetic acid, disodium salt (preferably as thedihydrate and, if desired, as the anhydrous form);ethylenediaminetetraacetic acid, tetrasodium salt (preferably as thehydrate); ethylenediaminetetraacetic acid, tripotassium salt (preferablyas the dihydrate); ethylenediaminetetraacetic acid, trisodium salt(preferably as the hydrate) and ethylenediaminetetraacetic acid disodiumsalt, USP (preferably as the dihydrate). In embodiments, pharmaceuticalcompositions described herein have an effective amount of a particulateformation inhibitor. In embodiments the excipients may include, e.g., anamino acid, urea, alcohol, ascorbic acid, phospholipids, proteins, suchas serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, andsodium chloride, liposomes, polyvinylpyrollidone, sugars, such asdextran, mannitol, sorbitol, and glycerol, propylene glycol andpolyethylene glycol (e.g., PEG-4000, PEG-6000), glycerol, glycine,and/or lipids.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes a solubilizing agent. For example, solubilizingagents may include, but are not limited to, acids, such as carboxylicacids, amino acids. In other examples, the solubilizing agents may besaturated carboxylic acids, unsaturated carboxylic acids, fatty acids,keto acids, aromatic carboxylic acids, dicarboxylic acids, tricarboxylicacids, α-hydroxy acids, amino acids, and combinations thereof.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes a solubilizing agent such as formic acid, aceticacid, propionic acid, butyric acid, valeric acid, caproic acid, enanthicacid, caprylic acid, pelargonic acid, capric acid, lauric acid, stearicacid, acrylic acid, docosahexaenoic acid, eicosapentaenoic acid, pyruvicacid, benzoic acid, salicylic acid, aldaric acid, oxalic acid, malonicacid, malic acid, succinic acid, glutaric acid, adipic acid, citricacid, lactic acid, alanine, arginine, aspargine, aspartic acid,cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, praline, serine, threonine, tryptophan,tyrosine, valine, and combinations thereof.

In embodiments, the solubilizing agent is selected from acetic acid,salts thereof, and combinations thereof, (e.g., acetic acid/sodiumacetate), citric acid, salts thereof and combinations thereof (e.g.,citric acid/sodium citrate), DL arginine, L-arginine and histadine. Inembodiments, the solubilizing agent is DL-arginine. In embodiments, thesolubilizing agent is L-arginine. In embodiments, the solubilizing agentis acetic acid/sodium acetate. In embodiments, the solubilizing agent iscitric acid/sodium citrate.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient renders the composition isotonic. Isotonic pharmaceuticalcompositions herein may be achieved by adding an appropriate quantity ofsodium chloride, glucose, laevulose, dextrose, mannitol, or postassiumchloride, or calcium chloride, or calcium gluconoglucoheptonate, ormixtures thereof. For example, the excipients may include one or moretonicity agents, such as, e.g., sodium chloride, potassium chloride,glycerin, mannitol, and/or dextrose. Tonicity agents may be used tominimize tissue damage and irritation, reduce hemolysis of blood cells,and/or prevent electrolyte imbalance. For example, the parenteralcompositions may be an aqueous solution including sodium chloridewherein the composition is isotonic. In embodiments, the isotonizingagent is sodium chloride. In embodiments, the concentration of theisotonizing agent is between about 0.01 and about 2.0 weight percent. Inembodiments, the pharmaceutical compositions may comprise up to about10% isotonizing agent. In embodiments the pharmaceutical compositionsmay comprise up to about, e.g., 0.25%, 0.5%, 1%, 2.5% isotonizing agent.In embodiments the amount of isotonizing agent in the pharmaceutical isbetween about, e.g., 0.01% to 1%, 0.1% to 1%, 0.25% to 1%, or 0.5% to1%.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes a free radical antagonist. In embodiments, the freeradical antagonist is ascorbic acid, ascorbic acid derivatives, organiccompounds having at least one thiol, alkyl polyhydroxylated, andcycloalkyl polyhydroxylated compounds, and combinations thereof.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes a free radical scavenger selected from thiolyglycolicacid, thiolacetic acid, dithiothreitol, reduced glutathion, thiourea,α-thioglycerol, cystein, aceticystein, mercaptoethane sulfonic acid andcombinations thereof.

In embodiments, provided herein are pharmaceutical of an activesubstance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes ribolflavin, dithiothreitol, sodium thiosulfate,thiourea, ascorbic acid, methylene blue, sodium metabisulfite, sodiumbisulfite, propyl gallate acetylcysteine, phenol, acetone sodiumbisulfate, ascorbic acid, ascorbic acid esters, butylhydroxyanisol(BHA), Butylhydroxytoluene (BHT), cysteine, nordihydroguiaretic acid(NDGA), monothioglycerol, sodium bisulfite, sodium metabisulfate,tocophenols, and/or glutathione.

In embodiments, provided herein are pharmaceutical compositions of anactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, and an excipient wherein theexcipient includes a preservative. In embodiments, the preservative isselected from benzalkonium chloride, benzethonium chloride, benzylalcohol, chlorobutanol, chlorocresol, metacresol, Phenol, phenylmercuricnitrate, phenylmercuric acetate, methyl p-hydroxybenzoate, propylp-hydroxybenzoate, butyl p-hydroxybenzoate, and thimerosal. In otherembodiments, the preservative is selected from the group consisting ofphenol, meta-cresol, benzyl alcohol, parabens (e.g., methyl, propyl,butyl), benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuricsalts (e.g., acetate, borate, or nitrate), and combinations thereof.

In embodiments, the compositions herein include a co-solvent. Forexample, in some instances the solubility of gaboxadol may be well belowthe therapeutic dose and therefore a co-solvent system may be used. Aco-solvent is a mixture of solvents that may be used to achievesufficiently high solubility and may increase the stability. Forexample, co-solvents may be a water-miscible organic solvents, such asethanol, propylene, glycol, Capmul PG, propylene glycol, glycerin,polyethylene glycol, sorbitol, dimethylacetamide, and/ordimethylsulfoxide (DMSO). In embodiments, the cosolvent may comprise upto about 75% of the pharmaceutical composition. In other embodiments theamount of cosolvent used include up to about, e.g., 1%, 5%, 10%, 15%,25%, 40%, 50%, of the pharmaceutical composition.

The dosage forms may be prepared, for example, by mixing of anallosteric modulator and/or gaboxadol, or a pharmaceutically acceptablesalt thereof, and one or more excipients (e.g., buffering agents,solubilizing agents, tonicity agents, antioxidants, chelating agents,antimicrobial agents and/or preservatives) in a blender under sterileconditions until a uniform blend is obtained. Pre-sterilized vials maythen be filled with an appropriate amount of the sterile blend. Thepredetermined amount of sterile blend may then be mixed with a solvent,e.g., water, saline, about 5-10% sugar (e.g., glucose, dextrose)solution and combinations thereof prior to administration. In addition,the solution may be frozen and thawed prior to further processing.

The excipients may be used in solid or in solution form. When used insolid form, the excipients and an allosteric modulator and/or gaboxadol,or a pharmaceutically acceptable salt thereof, may be mixed together asdescribed above, and then solvent added prior to parenteraladministration. When used in solution form, the allosteric modulatorand/or gaboxadol, or a pharmaceutically acceptable salt thereof, may bemixed with a solution of the excipient prior to parenteraladministration.

Parenteral solutions including an allosteric modulator and/or gaboxadol,or a pharmaceutically acceptable salt thereof, may be prepared by mixingthe required amount of allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, which may be purified prior touse in parenteral fluids such as D5W, distilled water, saline or PEG andadjusting the pH of this solution between 6.8-8. The process may becarried out at room temperature, or to increase concentration, thesolution may be warmed appropriately. Other solvents such as PEG 400,600, polypropylene glycol or other glycols can be used to enhancesolubility. The resulting solutions after cooling to room temperature,may be sterilized by known means such as ultrafiltration using, e.g.,0.45 micron filter or ethylene oxide treatment or heating and may bepackaged into ampules, vials or pre-filled syringes suitable fordispensing a sterile parenteral formulation.

When administered, the parenteral compositions herein provide a time ofmaximum plasma concentration (T_(max)) for gaboxadol in human patientsof about 1 or more hours (e.g., about 1.5 or more hours). Inembodiments, a T_(max) of gaboxadol in human patients ranging frombetween, e.g., about 1 to about 5 hours, about 1 to about 4 hours, about1 to about 3 hours, about 1 to about 2 hours. In embodiments, a T_(max)for gaboxadol in human patients of more than about 1.5 is observed. Inembodiments, a T_(max) for gaboxadol in human patients of less thanabout 3 hours is observed. The time of maximum plasma concentration ismeasured once infusion is complete.

In embodiments herein a dosage form includes from about 1 mg to about500 mg gaboxadol, wherein parenteral administration (e.g.,intramuscular, intravenous, subcutaneous, intraperitoneal, orintrathecal) of the dosage form provides an in vivo plasma profile forgaboxadol encompassing a mean AUC_(0-∞) of more than about 25 ng·hr/ml.In embodiments, single dose administration of the dosage form providesan in vivo plasma profile for gaboxadol encompassing a mean AUC_(0-∞) ofmore than about, e.g., 50 ng·hr/ml, 75 ng·hr/ml, 150 ng·hr/ml, 250ng·hr/ml, 500 ng·hr/ml, 1000 ng·hr/ml, or 1500 ng·hr/ml.

In embodiments, the dosage form includes from about 1 mg to about 500 mggaboxadol, wherein administration of the dosage form provides an in vivoplasma profile for gaboxadol encompassing a mean C_(max) of less thanabout 10000 ng/ml. In embodiments, single dose administration of thecompositions provide an in vivo plasma profile for gaboxadol of a meanC_(max) of less than about, e.g., 5000 ng/ml, 2500 ng/ml, 1000 ng/ml,500 ng/ml, 250 ng/ml, or 100 ng/ml.

In embodiments, pharmaceutical compositions for parenteraladministration include gaboxadol or a pharmaceutically acceptable saltthereof wherein parenteral administration exhibits a pharmacokineticprofile of a T_(max) at about 1 to about 120 minutes afteradministration of the parenteral composition; followed by a plasma drugconcentration of at least 50% C_(max) for a duration of about 90 toabout 360 minutes. In embodiments, parenteral administration ofgaboxadol is followed by a plasma drug concentration of at least 50%C_(max) for a duration of, e.g., about 10 to about 60 minutes, about 15to about 90 minutes, about 30 to about 120 minutes, about 60 to about180 minutes, about 90 to about 180 minutes.

In embodiments, stable pharmaceutical compositions are provided in unitdosage form in a vial or ampoule suitable for parenteral administrationhaving a therapeutically effective amount of allosteric modulator and/orgaboxadol, or a pharmaceutically acceptable salt thereof, dissolved insterile water to form a solution wherein the composition issubstantially free of any excipient, organic solvent, buffer, acid,base, salt other than allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof. In embodiments, thepharmaceutical composition remains sufficiently soluble and is capableof direct administration. In embodiments, the pharmaceutical compositionis capable of storage in the absence of an inert atmosphere for at least6 months.

In embodiments, provided herein are stable pharmaceutical compositionsin unit dosage form in a vial or ampoule suitable for parenteraladministration having a therapeutically effective amount of allostericmodulator and/or gaboxadol, or a pharmaceutically acceptable saltthereof, dissolved in sterile water to form a solution wherein thecomposition is free of any excipient, organic solvent, buffer, acid,base, salt other than allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof. In embodiments, thepharmaceutical composition remains sufficiently soluble and is capableof direct administration. In embodiments, the pharmaceutical compositionis capable of storage in the absence of an inert atmosphere for at least6 months.

In embodiments, stable pharmaceutical compositions suitable forparenteral administration include allosteric modulator and/or gaboxadol,or a pharmaceutically acceptable salt thereof, in an aqueous solutionhaving an osmolarity between 225 and 350 mOsm/kg and at a pH in therange between 7.0 and 8.0. In embodiments, the aqueous solution has anosmolarity between 270 and 310. In embodiments, the aqueous solution hasa pH in the range between 7.2 and 7.8.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical and a second pharmaceutical composition includinggaboxadol or a pharmaceutically acceptable salt thereof, and/or anallosteric modulator, wherein the second pharmaceutical composition thatprovides a stable in vivo plasma profile having a mean AUC_(0-∞) of atleast about, e.g., 25%, 30%, 35%, 40%, 45% or 50% less than the firstpharmaceutical composition. In embodiments, the composition providesimprovement of next day functioning of the patient. For example, thecomposition may provide improvement in one or more symptoms for morethan about, e.g., 6 hours, 8 hours, 10 hours, or 12 hours afteradministration of the first and/or second pharmaceutical composition.

In embodiments, parenteral compositions may be administered as needed,e.g., once, twice, thrice or four or more times daily, or continuouslydepending on the patient's needs. In embodiments, the parenteralcompositions may be administered immediately or as soon thereafter asseizures start. In embodiments, the parenteral compositions may beadministered as soon as warning signs of a seizure are exhibited such asauras, unusual smells, usual feelings, etc.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical dosage including a sub-therapeutic dosage of anallosteric modulator wherein the composition provides improvement formore than 6 hours after administration.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical dosage including a sub therapeutic dosage of gaboxadol ora pharmaceutically acceptable salt thereof wherein the compositionprovides improvement for more than 6 hours after administration.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical composition including an allosteric modulator and asecond pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the secondpharmaceutical composition provides an in vivo plasma profile having amean AUC_(0-∞) of less than about 900 ng·hr/ml. In embodiments, thesecond pharmaceutical composition provides an in vivo plasma profilehaving a AUC_(0-∞) of less than about, e.g., 800 ng·hr/ml, 750 ng·hr/ml,700 ng·hr/ml, 650 ng·hr/ml, or 600 ng·hr/ml. In embodiments, the secondpharmaceutical composition provides an in vivo plasma profile having aAUC_(0-∞) of less than about, e.g., 550 ng·hr/ml, 500 ng·hr/ml, 450ng·hr/ml, 400 ng·hr/ml, or 350 ng·hr/ml. In embodiments, the secondpharmaceutical composition provides an in vivo plasma profile having aAUC_(0-∞) of less than about, e.g., 300 ng·hr/ml, 250 ng·hr/ml, 200ng·hr/ml, 150 ng·hr/ml, or 100 ng·hr/ml. In embodiments, the first andsecond pharmaceutical composition are administered wherein thecompositions provide improvement of next day functioning of the patient.In embodiments, the first pharmaceutical composition providesimprovement in one or more symptom for more than, e.g., 6 hours, 8 hoursor 12 hours after administration of the first pharmaceuticalcomposition.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof a firstpharmaceutical composition including an allosteric modulator and asecond pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the first compositionprovides an in vivo plasma profile with a C_(max) that is more thanabout 50% greater than the C_(max) provided by the administration of thesecond pharmaceutical composition. As used herein the C_(max) providedby the administration of the second pharmaceutical composition may ormay not include the plasma profile contribution of the firstpharmaceutical composition. In embodiments, the administration of thesecond pharmaceutical composition does not include the plasma profilecontribution of the first pharmaceutical composition. In embodiments,the first composition provides an in vivo plasma profile having aC_(max) that is more than about e.g., 60%, 70%, 80%, or 90% greater thanthe C_(max) provided by the administration of the second pharmaceuticalcomposition.

In embodiments, the T_(max) of the first pharmaceutical composition isless than 3 hours. In embodiments, the T_(max) of the firstpharmaceutical composition is less than 2.5 hours. In embodiments, theT_(max) of the first pharmaceutical composition is less than 2 hours. Inembodiments, the T_(max) of the first pharmaceutical composition is lessthan 1.5 hours. In embodiments, the T_(max) of the first pharmaceuticalcomposition is less than 1 hour.

In embodiments, the first pharmaceutical composition provides adissolution of at least about 80% within the first 20 minutes ofadministration to a patient in need thereof. In embodiments, the firstpharmaceutical composition provides a dissolution of at least about,e.g., 85%, 90% or 95% within the first 20 minutes of administration to apatient in need thereof. In embodiments, the first pharmaceuticalcomposition provides a dissolution of at least 80% within the first 10minutes of administration to a patient in need thereof.

In embodiments the first and/or the second pharmaceutical compositionsare sub therapeutic dosages. A sub therapeutic dosage is an amount ofactive substance, e.g., allosteric modulator and/or gaboxadol, or apharmaceutically acceptable salt thereof, that is less than the amountrequired for a therapeutic effect. In embodiments, a sub therapeuticdosage is an amount of allosteric modulator or a pharmaceuticallyacceptable salt thereof that alone may not provide improvement in atleast one symptom of the epileptic disorder but is sufficient tomaintain such improvement. In embodiments, a sub therapeutic dosage isan amount of gaboxadol pharmaceutically acceptable salt thereof thatalone may not provide improvement in at least one symptom of theepileptic disorder but is sufficient to maintain such improvement. Inembodiments, the methods provide administering a first pharmaceuticalcomposition that provides improvement in at least one symptom of anepileptic disorder and a second composition that maintains theimprovement. In embodiments, after administration of the firstpharmaceutical composition, the second pharmaceutical composition mayprovide a synergistic effect to improve at least one symptom of anepileptic disorder. In embodiments the second pharmaceutical compositionmay provide a synergistic effect to improve at least one symptom of anepileptic disorder.

In embodiments, provided herein are methods of treating an epilepticdisorder including administering to a patient in need thereof apharmaceutical composition including a first pharmaceutical dosagewherein the composition provides improvement for more than 6 hours afteradministration and a second pharmaceutical composition including a subtherapeutic dosage of gaboxadol or a pharmaceutically acceptable saltthereof.

Administration of the first and second pharmaceutical compositions maybe simultaneous or separated by an interval of time to achieveimmediate, intermediate or long-term improvement in at least onesymptom. In embodiments, the first and second pharmaceutical compositionmay be administered 6 hours apart. In embodiments, the first and secondpharmaceutical composition may be administered 12 hours apart. Inembodiments, the first and second pharmaceutical compositions mayadministered within, e.g., 15 minutes, 30 minutes, 1 hour, 2 hours, 6hours, 12 hours, 18 hours, 24 hours etc. In embodiments, the first andsecond pharmaceutical composition may be administered together. Inembodiments, the first and second pharmaceutical compositions mayadministered separated by at least, e.g., 15 minutes, 30 minutes, 1hour, 2 hours, 12 hours, 18 hours, 24 hours etc. In embodiments,improvement in at least one symptom of an epileptic disorder for morethan 8 hours after administration to the patient is provided. Inembodiments, improvement for more than about, e.g., 10 hours, 12 hours,15 hours, 18 hours, 20 hours, or 24 hours after administration to thepatient is provided.

In embodiments, the administration of the first and secondpharmaceutical composition may provide a synergistic effect to improveat least one symptom of an epileptic disorder.

In embodiments, the first and/or the second pharmaceutical compositioninclude any of the aforementioned amounts of active substance, e.g.,allosteric modulator and/or gaboxadol a pharmaceutically acceptable saltthereof.

In embodiments, the first and/or the second pharmaceutical compositioninclude 5 mg to 15 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mgto 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18mg, or 18 mg to 20 mg active substance, e.g., allosteric modulatorand/or gaboxadol.

In embodiments, the first and/or the second pharmaceutical compositioninclude 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg,7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg active substance, e.g.,allosteric modulator and/or gaboxadol or amounts that are multiples ofsuch doses. In embodiments, the first pharmaceutical compositionsinclude 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allostericmodulator. In embodiments, the second pharmaceutical compositionsinclude 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg of an allostericmodulator.

In embodiments, methods of treating epileptic disorders includeadministration of an allosteric modulator and/or gaboxadol or apharmaceutically acceptable salt thereof, in combination with one ormore other active compounds. The combination therapies can includeadministration of the active agents together in the same admixture, orin separate admixtures. In embodiments, the pharmaceutical compositionincludes two, three, or more active agents. In embodiments, thecombinations result in a more than additive effect on the treatment ofthe disease or disorder. Thus, treatment is provided of an epilepticdisorder with a combination of agents that combined, may provide asynergistic effect that enhances efficacy.

In embodiments, gaboxadol or a pharmaceutically acceptable salt thereof,is administered in combination with conventional therapy for seizures,epilepsy, or one of the other disorders disclosed herein. For example,common conventional therapies for seizures and epilepsy includeantiepileptic drugs and non-antiepileptic drug treatments such as lowcarbohydrate diet (e.g., ketogenic diets, such as classical diet, mediumchain triglyceride (MCT) diet, modified Atkins diet (MAD), and lowglycemic index treatment (LGIT)), intravenous immunoglobulin, steroids,elimination diet, valgus nerve stimulation, corticetomy, and multiplesubpial transections.

Common antiepileptic and anticonvulsive active compounds that may beused in combination with an allosteric modulator and/or gaboxadol or apharmaceutically acceptable salt thereof include, but are not limitedto, acetazolamide, eslicarbazepine acetate, ethosuximide, gabapentin,lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine,perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone,retigabine, rufinamide, sodium valproate, stiripentol, tiagabine,topiramate, vigabatrin, and zonisamide.

The disclosed compounds, such as gaboxadol or pharmaceuticallyacceptable salts thereof, or an allosteric modulator, pharmaceuticallyacceptable salts, derivatives and/or analogues thereof, can be usedindividually as a monotherapy as the only active agent. In embodiments,methods are provided of treating epileptic disorders using an allostericmodulator or a pharmaceutically acceptable salt thereof. In embodiments,methods of treating epileptic disorders include administration of anallosteric modulator, pharmaceutically acceptable salts, derivativesand/or analogues thereof in combination with one or more other activeagent, e.g., allosteric modulator or gaboxadol. The combinationtherapies can include administration of the active agent, e.g.,allosteric modulator or gaboxadol, together in the same admixture, or inseparate admixtures. In embodiments, the pharmaceutical compositionincludes two, three, or more active agents. In embodiments, thecombinations result in a more than additive effect on the treatment ofthe disease or disorder. Thus, treatment is provided of an epilepticdisorder with a combination of agents that combined, may provide asynergistic effect that enhances efficacy.

In embodiments, gaboxadol or pharmaceutically acceptable salts thereof,or an allosteric modulator, pharmaceutically acceptable salts,derivatives and/or analogues thereof, or both, is administered incombination with conventional therapy for seizures, epilepsy, or one ofthe other disorders disclosed herein. For example, common conventionaltherapies for seizures and epilepsy include antiepileptic drugs andnon-antiepileptic drug treatments such as low carbohydrate diet (e.g.,ketogenic diets, such as classical diet, medium chain triglyceride (MCT)diet, modified Atkins diet (MAD), and low glycemic index treatment(LGIT)), intravenous immunoglobulin, steroids, elimination diet, valgusnerve stimulation, corticetomy, and multiple subpial transections.

Common antiepileptic and anticonvulsive active compounds that may beused in combination with an allosteric modulator include, but are notlimited to, acetazolamide, carbamazepine, clobazam, clonazepam,eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide,lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel,piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine,rufinamide, sodium valproate, stiripentol, tiagabine, topiramate,vigabatrin, and zonisamide.

In embodiments, a co-therapy of an allosteric modulator, apharmaceutically acceptable salt thereof, or a derivative thereof andgaboxadol or a pharmaceutically acceptable salt thereof is effective toreduce seizure frequency or severity in the subject greater than eithercompound is administered alone. In embodiments, the co-therapy producesa more than additive result compared to compounds administeredindividually.

In embodiments, the subject may be started at a low dose and the dosageis escalated. In this manner, it can be determined if the drug is welltolerated in the subject. Dosages can be lower for children than foradults.

In embodiments, such as combination therapies, a dose of gaboxadol forchildren can be 0.1 mg/kg to 1 mg/kg, and the dose for an allostericmodulator may be 0.01 mg/kg to 0.1 mg/kg. In embodiments, theweight/weight ratio of gaboxadol and an allosteric modulator can be10-to-1. However, the dosing ratio based on milligrams of activepharmaceutical ingredient (API) can range from 0.1-to-1 to 100-to-1 ofgaboxadol-to-an allosteric modulator respectively.

Effective treatment of an epileptic disorder (e.g., acute repetitiveseizure) herein may be established by showing reduction in the frequencyof seizures (e.g., more than 50%) after a period of time compared withbaseline. For example, after a baseline period of 1 month, the patientsmay be randomly allocated gaboxadol or an allosteric modulator orplacebo as add-on therapy to standard therapies, such as valproate andclobazam, during a double-blind period of 2 months. Primary outcomemeasurements may include the percentage of responders on gaboxadol or anallosteric modulator and on placebo, defined as having experienced atleast a 50% reduction of clonic (or tonic-clonic) seizure frequencyduring the second month of the double-blind period compared withbaseline. Patients who present with status epilepticus during thedouble-blind period may be regarded as non-responders. Secondaryoutcomes may include the absolute count of clonic (or tonic-clonic)seizures during the second month of the double-blind period (normalizedto 30 days, by dividing the raw count by the exact number of days ofobservation and multiplying by 30) and the percentage of change frombaseline.

The effectiveness of gaboxadol and/or an allosteric modulator for thetreatment of a disclosed epileptic disorder, e.g., associated withDravet syndrome or Lennox-Gastaut syndrome, may be established in othercontrolled studies. For example, a randomized, double-blind,placebo-controlled study consisting of a 4-week baseline period followedby a 3-week titration period and 12-week maintenance period may be usedin patients age 2-54 years with a current or prior diagnosis of Dravetsyndrome or LGS. Multiple target maintenance doses of gaboxadol and/oran allosteric modulator may be tested according to patient body weightand specific dosing regime. A primary efficacy measure may include thepercent reduction in the weekly frequency of drop seizures (atonic,tonic, or myoclonic), also known as drop attacks, from the 4-weekbaseline period to 12-week maintenance period. Thus, efficacy may bemeasured as percentage reduction in weekly seizure (e.g., atonic, tonic,or myoclonic) frequency from baseline of, e.g., 0 to <20, 20 to <40, 40to <60, 60 to <80, 80 to <100.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosure herein belongs.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, preferably up to 10%, more preferably up to 5%,and more preferably still up to 1% of a given value. Alternatively,particularly with respect to biological systems or processes, the termcan mean within an order of magnitude, preferably within 5-fold, andmore preferably within 2-fold, of a value.

As used herein, the term “treating” or “treatment” refers toalleviating, attenuating or delaying the appearance of clinical symptomsof a disease or condition in a subject that may be afflicted with orpredisposed to the disease or condition, but does not yet experience ordisplay clinical or subclinical symptoms of the disease or condition. Incertain embodiments, treating” or “treatment” may refer to preventingthe appearance of clinical symptoms of a disease or condition in asubject that may be afflicted with or predisposed to the disease orcondition, but does not yet experience or display clinical orsubclinical symptoms of the disease or condition. “Treating” or“treatment” may also refer to inhibiting the disease or condition, e.g.,arresting or reducing its epileptic or at least one clinical orsubclinical symptom thereof “Treating” or “treatment” further refers torelieving the disease or condition, e.g., causing regression of thedisease or condition or at least one of its clinical or subclinicalsymptoms. The benefit to a subject to be treated may be statisticallysignificant, mathematically significant, or at least perceptible to thesubject and/or the physician. Nonetheless, prophylactic (preventive) andtherapeutic treatment are two separate embodiments of the disclosureherein.

“Effective amount” or “therapeutically effective amount” means a dosagesufficient to alleviate one or more symptom of a disorder, disease, orcondition being treated, or to otherwise provide a desiredpharmacological and/or physiologic effect.

“Improvement” refers to the treatment of symptoms or conditionsassociated with epileptic disorders, measured relative to at least onesymptom or condition of the metabolic disease.

“Improvement in next day functioning” or “wherein there is improvementin next day functioning” refers to improvement after waking from anovernight sleep period wherein the beneficial effect of administrationof one or more of gaboxadol or a pharmaceutically acceptable saltthereof alone, or an allosteric modulator alone, or gaboxadol incombination an allosteric modulator, applies to at least one symptom orcondition associated with an epileptic disorder and is discernable,either subjectively by a patient or objectively by an observer, for aperiod of time, e.g., immediately, 1 hour, 2 hours, hours, 3 hours, 4hours, 5 hours, 6 hours, 12 hours, 24 hours, etc. after waking.

“Composition”, “pharmaceutical composition”, “formulation”,“pharmaceutical formulation” are used interchangeably herein.“Composition”, “pharmaceutical composition”, “formulation”,“pharmaceutical formulation” encompass dosage forms. Dosage forms canencompass unit doses.

“Pharmaceutically acceptable” refers to molecular entities andcompositions that are “generally regarded as safe”, e.g., that arephysiologically tolerable and do not typically produce an allergic orsimilar untoward reaction, such as gastric upset and the like, whenadministered to a human. In embodiments, this term refers to molecularentities and compositions approved by a regulatory agency of the federalor a state government, as the GRAS list under section 204(s) and 409 ofthe Federal Food, Drug and Cosmetic Act, that is subject to premarketreview and approval by the FDA or similar lists, the U.S. Pharmacopeiaor another generally recognized pharmacopeia for use in animals, andmore particularly in humans.

As used herein, the term “prevention” or “preventing” means toadminister a composition to a subject or a system at risk for or havinga predisposition for one or more symptoms caused by a disease ordisorder to facilitate cessation of a particular symptom of the diseaseor disorder, a reduction or prevention of one or more symptoms of thedisease or disorder, a reduction in the severity of the disease ordisorder, the complete ablation of the disease or disorder,stabilization or delay of the epileptic or progression of the disease ordisorder.

“Prodrug”, as used herein, refers to a pharmacological substance (drug)that is administered to a subject in an inactive (or significantly lessactive) form. Once administered, the prodrug is metabolized in the body(in vivo) into a compound having the desired pharmacological activity.

“Analog” “analogue, and “derivative” are used herein interchangeably andrefer to a compound that possesses the same core as the parent compound,but may differ from the parent compound in bond order, the absence orpresence of one or more atoms and/or groups of atoms, and combinationsthereof. The derivative can differ from the parent compound, forexample, in one or more substituents present on the core, which mayinclude one or more atoms, functional groups, or substructures. Ingeneral, a derivative can be imagined to be formed, at leasttheoretically, from the parent compound via chemical and/or physicalprocesses.

“Stereoisomer”, as used herein, refers to isomeric molecules that havethe same molecular formula and sequence of bonded atoms (constitution),but which differ in the three dimensional orientations of their atoms inspace. Examples of stereoisomers include enantiomers and diastereomers.As used herein, an enantiomer refers to one of the two mirror-imageforms of an optically active or chiral molecule. Diastereomers (ordiastereoisomers) are stereoisomers that are not enantiomers(non-superimposable mirror images of each other). Chiral moleculescontain a chiral center, also referred to as a stereocenter orstereogenic center, which is any point, though not necessarily an atom,in a molecule bearing groups such that an interchanging of any twogroups leads to a stereoisomer. In organic compounds, the chiral centeris typically a carbon, phosphorus or sulfur atom, though it is alsopossible for other atoms to be stereocenters in organic and inorganiccompounds. A molecule can have multiple stereocenters, giving it manystereoisomers. In compounds whose stereoisomerism is due to tetrahedralstereogenic centers (e.g., tetrahedral carbon), the total number ofhypothetically possible stereoisomers will not exceed 2n, where n is thenumber of tetrahedral stereocenters. Molecules with symmetry frequentlyhave fewer than the maximum possible number of stereoisomers. A 50:50mixture of enantiomers is referred to as a racemic mixture.Alternatively, a mixture of enantiomers can be enantiomerically enrichedso that one enantiomer is present in an amount greater than 50%.Enantiomers and/or diasteromers can be resolved or separated usingtechniques known in the art. “Chirality” also includes axial and planarchirality.

The term “pharmaceutically acceptable salt”, as used herein, refers toderivatives of the compounds defined herein, wherein the parent compoundis modified by making acid or base salts thereof. Example ofpharmaceutically acceptable salts include but are not limited to mineralor organic acid salts of basic residues such as amines; and alkali ororganic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric acids; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic,oxalic, and isethionic salts. The pharmaceutically acceptable salts ofthe compounds can be synthesized from the parent compound, whichcontains a basic or acidic moiety, by conventional chemical methods. Forexample, gaboxadol may be formulated for administration to a patientusing pharmaceutically acceptable salts including acid addition salts, azwitter ion hydrate, zwitter ion anhydrate, hydrochloride orhydrobromide salt, or in the form of the zwitter ion monohydrate. Acidaddition salts, include but are not limited to, maleic, fumaric,benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acidaddition salts, as well as the 8-halotheophyllines, for example8-bromo-theophylline. In other suitable embodiments, inorganic acidaddition salts, including but not limited to, hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric or nitric acid addition salts may beused.

“Excipient” is a substance, other than the active drug substance, e.g.,gaboxadol, of a pharmaceutical composition, which has been appropriatelyevaluated for safety and are included in a drug delivery system toeither aid the processing of the drug delivery system during itsmanufacture; protect; support; enhance stability, bioavailability, orpatient acceptability; assist in product identification; or enhance anyother attributes of the overall safety and effectiveness of the drugdelivery system during storage or use.

“Stabilizer” or “stabilizing amount” refers to an amount of one or moreexcipients included in the parenteral compositions that providesufficient stability but do not adversely affect the bioavailability,safety and/or efficacy of allosteric modulator and/or gaboxadol orpharmaceutically acceptable salt thereof used in the composition.

“Stable” means that there is substantially no degradation of thegaboxadol or pharmaceutically acceptable salt thereof after a specifiedperiod of time, e.g., after 3 months or 6 months.

“Soluble” means that the solution of allosteric modulator and/orgaboxadol or pharmaceutically acceptable salt thereof does not turn hazyand/or there is substantially no precipitate in the solution.

“Sufficiently soluble” means that the particle content is sufficientlylow, and the material is sufficiently sterile such that it is useful forparenteral administration. For example, the number of particles in aliquid composition should be, e.g., less than 6,000 10 μm particlesshould be present in a volume of 10 ml solvent, preferably less than10,000, less than 5,000, less than 3,000, less than 1,000, or less than400 10 μm particles. In some examples, the number of particles in aliquid composition should be less than 1000, less than 600, or less than200 25 μm particles in the 10 ml volume.

“Local site compatible” herein shall mean the composition is tolerant atthe site of injection or infusion, thus minimizing side effects, such aslocal skin irritations or venous irritations, including inflammatoryreactions at the infusion site. The parenteral compositions herein mayhave less side reactions than conventional products, such as skinirritation or phlebitis.

“Purified” as used herein refers to material that has been isolatedunder conditions that reduce or eliminate the presence of unrelatedmaterials, i.e., contaminants, including native materials from which thematerial is obtained. As used herein, the term “substantially free” isused operationally, in the context of analytical testing of thematerial. Preferably, purified material substantially free ofcontaminants is at least 95% pure; more preferably, at least 97% pure,and more preferably still at least 99% pure. Purity can be evaluated,for example, by chromatography or any other methods known in the art. Inembodiments, purified means that the level of contaminants is below alevel acceptable to regulatory authorities for safe administration to ahuman or non-human animal.

“Ready-to-use” with reference to the compositions herein shall mean thepreparation in the reconstituted form, with standardized concentrationand quality, prefilled in the single-use container, such as glass vials,infusion bags or syringes, ready for direct administration to thepatient.

“Direct administration” with reference to the compositions herein shallmean the immediate administration, i.e., without further dilution,premixing with other substances or otherwise changing the composition orformulation of the composition. Such composition is typically directlydischarged from an infusion device and administered via a vascularaccess port or through a central line.

“Dosage” is intended to encompass a formulation expressed in terms ofμg/kg/day, μg/kg/hr, mg/kg/day or mg/kg/hr. The dosage is the amount ofan ingredient administered in accordance with a particular dosageregimen. A “dose” is an amount of an agent administered to a mammal in aunit volume or mass, e.g., an absolute unit dose expressed in mg or μgof the agent. The dose depends on the concentration of the agent in theformulation, e.g., in moles per liter (M), mass per volume (m/v), ormass per mass (m/m). The two terms are closely related, as a particulardosage results from the regimen of administration of a dose or doses ofthe formulation. The particular meaning in any case will be apparentfrom context.

“Patient” and “subject” are used interchangeably herein and include, butnot limited to, primates such as humans, canines, porcine, ungulates,rodents, poultry, and avian.

“Co-administered with”, “in combination with”, “administered incombination with”, “a combination of”, “administered along with”, or“co-therapy”, may be used interchangeably and mean that two or moreagents are administered in the course of therapy. The agents may beadministered together at the same time or separately in spaced apartintervals. The agents may be administered in a single dosage form or inseparate dosage forms.

“PK” refers to the pharmacokinetic profile. C_(max) is defined as thehighest plasma drug concentration estimated during an experiment(ng/ml). T_(max) is defined as the time when C_(max) is estimated (min).AUC_(0-∞) is the total area under the plasma drug concentration-timecurve, from drug administration until the drug is eliminated (ng·hr/mlor μg·hr/ml). The area under the curve is governed by clearance.Clearance is defined as the volume of blood or plasma that is totallycleared of its content of drug per unit time (ml/min).

EXAMPLES

The Examples provided herein are included solely for augmenting thedisclosure herein and should not be considered to be limiting in anyrespect.

Example 1 Gaboxadol Plasma Concentration Profiles

The following Example provides the plasma concentration profiles anddose proportionality of gaboxadol monohydrate following single oraldoses ranging from 2.5 to 20 mg. The absolute bioavailability ofgaboxadol monohydrate capsules ranging from 2.5 to 20 mg is alsoassessed.

This study was composed of separate groups of 10 healthy adult subjects(at least 4 of each gender) who participated in a 6-period,double-blind, randomized, crossover study designed to access the doseproportionality and absolute bioavailabilty of 5 single oral doses ofgaboxadol across the dose range of 2.5 to 20 mg. The order in which thesubjects received the 5 single oral doses of gaboxadol (2.5; 5; 10; 15;and 20 mg) was randomized within Treatment Periods 1 through 5. Eachsubject was expected to complete all 6 treatment periods and there was awashout of at least 4 days between each treatment period.

Each oral dosing within Treatment Periods consisted of 2 capsules oftest drug taken simultaneously at each scheduled dosing. The treatmentdesignations for the orally administered study drugs were as follows:Treatment A—one 2.5 mg gaboxadol capsule and 1 matching placebo capsule;Treatment B—one 5 mg gaboxadol capsule and 1 matching placebo capsule;Treatment C—one 10 mg gaboxadol capsule and 1 matching placebo capsule;Treatment D—one 15 mg gaboxadol capsule and 1 matching placebo capsule;and Treatment E—20 mg gaboxadol (two 10 mg gaboxadol capsules). Subjectsreceived their study drug after an overnight fast with 240 mL of waterin the morning about 8:00 AM. Water was permitted ad libitum exceptwithin 1 hour prior to and after study drug administration. No food wasallowed for 4 hours post dose.

For each subject in each treatment, plasma and urine samples werecollected over 16 hours post-dosing for the determination ofpharmacokinetic parameters (e.g., AUC, C_(max), T_(max), apparentt_(1/2), cumulative urinary excretion, renal clearance, clearance, andsteady-state volume of distribution, as appropriate). AUC and C_(max)for gaboxadol were potency adjusted to facilitate comparison ofpharmacokinetic data across studies. Table 1 provides the individualpotency-adjusted pharmacokinetic parameters of gaboxadol followingsingle oral doses (2.5, 5, 10, 15, and 20 mg).

TABLE 1 Pharmacokinetic parameters for gaboxadol following oral and IVadministration Pharmacokinetic parameters for gaboxadol following oraland IV administration Geometric Mean (N = 10) 10 mg 10 mg Parameter 2.5mg 5 mg Oral I.V. 15 mg 20 mg Slope (90% CI)^(††) AUC_(0-∞) 90 171 346380 539 669 0.98 (0.95, 1.01) (ng · hr/mL) C_(max) (ng/mL)^(†) 61 110232 212 382 393 0.95 (0.88, 1.02) T_(max) (hr)^(‡) 0.5 0.6 0.5 — 0.5 0.6Apparent t_(1/2) 1.5 1.5 1.6 1.5 1.5 1.6 (hr)^(§) CL/F 461 488 476 438469 499 (mL/min) 

F_(e) (%) 43 45 53 53 50 53 CL_(R) (mL/min) 196 222 250 208 234 265 F(%) (90% 92% (0.86, 0.97) CI)^(#) ^(†)C_(coi) (ng/mL) for 10 mg. IV.^(‡)Median. ^(§)Harmonic Mean.

 CL (mL/min) for 10 mg IV. ^(#)Bioavailability relative to 10 mg I.V.reference based on pooled dose-adjusted (to 10 mg) oral AUC_(0-∞)values. ^(††)Dose proportionality assessment of oral treatments only.

Example 2 Assessment of Residual Effects Resulting from GaboxadolAdministration

This study was a double blind, double-dummy, randomized, active- andplacebo-controlled, single dose, 3-period crossover study, followed byan open-label, single-dose, single period study in healthy elderly maleand female subjects. Subjects were randomized to each of 3 treatments(Treatments A, B, and C) to be administered in a crossover manner overthe first 3 treatment periods. For Treatment A, subjects received asingle dose of gaboxadol 10 mg; for Treatment B, subjects received asingle dose of flurazepam 30 mg; and for Treatment C, subjects receiveda single dose of placebo. Doses were administered orally at bedtime onDay 1. Subjects were domiciled from early in the evening of dosing until˜36 hours post-dose (morning of Day 3) during each treatment period. Thesubjects who participated in treatment periods 1-3 participated in afourth treatment period. In this period, a single dose of gaboxadol 10mg (Treatment D) was administered orally in an open-label manner on themorning of Day 1 for PK of gaboxadol. There was at least a 14-daywashout between the doses of consecutive treatment periods. Studyparticipants included healthy, elderly male and female subjects between65 and 80 years of age, with a Mini Mental Status 24, weighing at least55 kg. All subjects received 10 mg gaboxadol monohydrate capsules and 30mg flurazepam (provided as 2×15 mg capsules), matching placebo wasprovided for both gaboxadol and flurazepam.

The primary endpoints evaluated included pharmacodynamics (measurementof psychomotor performance, memory, attention and daytime sleepiness thefollowing pm dosing), gaboxadol pharmacokinetics, and safety. Gaboxadol(single dose 10 mg) did not show residual effect 9 hours post-dose onthe primary endpoints Choice Reaction Time and Critical Flicker Fusion,whereas the active reference Flurazepam (30 mg single dose) showedsignificant effect on the same tests. In addition, gaboxadol did notshow any signs of residual effects on other measurements applied in thestudy (Multiple Sleep Latency Test (MSLT); Digit symbol substitutiontest (DSST), Tracking, Memory tests, Body Sway, and Leeds SleepEvaluation Questionnaire).

Example 3 Evaluation of the Ability of Allopregnanolone, Ganaxolone, andGaboxadol to Block Benzodiazepine-Resistant Status Epilepticus

Allopregnanolone, ganaxolone, and gaboxadol are evaluated for acuteanticonvulsant efficacy when administered with escalating doses at 30min after the onset of convulsive status epilepticus, a time-pointtypically resistant to benzodiazepines. Results obtained with theseagents are compared to those obtained from side-by-side studies withvehicle-treated animals.

Twenty-four hours prior to administration of the chemoconvulsantpilocarpine, male Sprague Dawley rats (n=10 time or treatment/group,100-125 g; Charles River Laboratories) are treated systemically withlithium chloride (127 mg/kg; (intraperitoneal (i.p.)). On the next day,the rats receive pilocarpine hydrochloride (50 mg/kg; i.p.) and aremonitored carefully for the presence or absence of convulsive seizureactivity. Administration of pilocarpine induces behavioral seizureswithin 5-20 min and any rat not showing convulsive seizure activitywithin 45 min of pilocarpine administration is excluded from furtherstudy. On the study day, the ability of each of the investigationalcompounds (allopregnanolone (ALLO), ganaxolone (GNX), or gaboxadol(GBD)) or vehicle (VEH) (40% hydroxypropyl B-cyclodextrin) to haltconvulsive status epilepticus in the Li-Pilo model of status epilepticusis evaluated with escalating doses administered i.p. 30 min after thefirst observed convulsive seizure. Throughout the study, theexperimenter conducting the behavioral observations is blinded totreatment conditions (i.e., allopregnanolone, ganaxolone, or gaboxadol).All rats are observed and scored for seizure severity for 120 min postdrug administration, and any accompanying behavioral effects are alsonoted by an experimenter blinded to treatment conditions. At theconclusion of the behavioral observation period, a 3 mL injection oflactated Ringer's solution is administered to all surviving rats toreplace any SE-induced fluid loss.

The dose of each of the investigational compounds (allopregnanolone,ganaxolone, or gaboxadol) is varied in groups of ten rats until at leasttwo points are established between the limits of 100% protection (nofurther convulsive seizures after 10 min of drug administration) and 0%protection. The dose of drug required to produce the desired endpoint in50% of animals (ED50 or TD50) and the 95% confidence interval iscalculated by a computer program based on the Probit method (Finney DJ.Probit Analysis. Cambridge University Press. 1971). This dose responseevaluation typically requires up to 5 treatment groups perinvestigational compound, for a total of up to 50 rats per compound.Thus, up to 150 rats can be used for the investigational compounds(allopregnanolone, ganaxolone, or gaboxadol) quantification, and thereis also one vehicle treatment group (n=10), such that the total numberof rodents in Study 1 is 160. All animals in the study are retained for24 hours following completion of the study for assessment of weightchange. The doses administered for allopregnanolone, ganaxolone, orgaboxadol are 0.5 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg.

Pharmacokinetics Sample Collection: Brains and plasma may be collectedfor assessment from a satellite cohort of rats for each dose (n=3rats/dose/compound; up to 45 rats in total). Plasma is collected fromtrunk blood after 10,000×g centrifugation for 10 min at 4° C. Theanticoagulant is lithiumheparin. Brains are snap frozen on dry ice. Allsamples are stored at −20° C. The testing procedure timeline is setforth in FIG. 2.

Dose-response curves are constructed and expressed as ED50 (95%confidence intervals) calculated for each investigational compound(allopregnanolone, ganaxolone, or gaboxadol) administered 30 min afterthe first observed convulsive seizure. In cases that the data does notpermit the calculation of an ED50 (95% confidence interval) because oflack of efficacy, the highest dose tested is noted. Additional measuresof effects, e.g., motor impairment, weight change post-SE, or survivalfrom SE for 24 hrs are also recorded during the studies for alltreatment conditions.

TABLE 2 Overall survival and protection results Protection 24-hourSurvival Compound (dose, mg/kg) (includes PK rats) (excludes PK rats)VEH (40% HPBCD) 0/13 (0%) 8/11^(#) (72%) ALLO (0.5 mg/kg) 0/13 (0%) 6/10(60%) GBD (0.5 mg/kg) 2/13 (15%) 7/10 (70%) GNX (0.5 mg/kg) 0/13 (0%)6/10 (60%) ALLO (2 mg/kg) 0/13 (0%) 7/10 (70%) GBD (2 mg/kg) 0/13 (0%)8/10 (80%) GNX (2 mg/kg) 0/13 (0%) 8/10 (80%) ALLO (5 mg/kg) 0/13 (0%)7/9 (72%) GBD (5 mg/kg) 0/13 (0%) 6/11^(#) (55%) GNX (5 mg/kg) 0/13 (0%)7/10 (70%) ALLO (10 mg/kg) 2/13 (15%) 9/10 (90%) GBD (10 mg/kg) 0/13(0%) 10/10 (100%)* GNX (10 mg/kg) 1/13 (7.7%) 9/10 (90%) ALLO (20 mg/kg)1/13 (7.7%) 9/10 (90%) GBD (20 mg/kg) 0/13 (0%) 7/9 (78%) GNX (20 mg/kg)4/13 (30.8%)* 9/10 (90%) *Significantly different from VEH, p < 0.05^(#)Spontaneous death during SE in PK group rat 110 min post-SE onset,but sample was collected.

FIG. 3 is a bar graph showing the percent protected versus dose withrespect to allopregnanolone, ganaxolone, or gaboxadol. FIG. 4 is a bargraph showing the 24-hour survival results based on dose with respect toallopregnanolone, ganaxolone, or gaboxadol. FIG. 5 is a bar graphshowing the number of observed seizures versus dose. FIG. 6A is a bargraph showing body weight changes 24 hours post-status epilepticus as afunction of percent loss versus dose. FIG. 6B is a bar graph showing 24hour body weight loss for 0.5 mg/kg dose groups. Dose-responseevaluation of treatment during benzodiazepine-resistant statusepilepticus suggests dose-dependent efficacy of ganaxolone(i.p.)—significant (p<0.02) improvement in protection at 20 mg/kg.Potential for inverted U-response profile of gaboxadol (i.p.)—p=0.071 at0.5 mg/kg. Significant improvements in 24-hour survival are shown forgabaxodol-treated rats (10 mg/kg).

Example 4 Prospective Study for the Characterization of the Ability ofAllopregnanolone, Ganaxolone, and Gaboxadol to BlockBenzodiazepine-Resistant Status Epilepticus

Initial dose-response studies with intraperitoneal (i.p.) administrationof allopregnanolone (ALLO), ganaxolone (GNX), and gaboxadol (GBD)suggests the potential for efficacy against benzodiazepine-resistantstatus epilepticus (Example 3). This study will assess the potential forsynergistic activity of gaboxadol with either allopregnanolone,ganaxolone, or the benzodiazepine, lorazepam (LZP), againstbenzodiazepine-resistant status epilepticus in the Li-Pilo model inrats. Specifically, gaboxadol at low-doses (e.g. 0.5 mg/kg) will beadministered in combination with a fixed dose of eitherallopregnanolone, ganaxolone, or lorazepam. The doses ofallopregnanolone and ganaxolone will be those that were previously foundto confer anticonvulsant effect in Example 3 (Table 2). The dose oflorazepam will be 2 mg/kg (Walton and Treiman. 1990. Neurology 40:990-994 1990). The activity of each compound will also be evaluatedalone. A vehicle-treatment group will be included. At 30 min post-statusepilepticus onset, a single i.p. dose of each dose or dose combination(Table 3) will be administered to rats (n=13/group). Rats will beobserved for presence or absence of further convulsive activity.

TABLE 3 Investigational Compounds and Combinations to be Evaluated (n =13 rats/treatment group with n = 3 rats sacrificed for PK analysis).Compound Dose (all i.p.) GBD 0.25 mg/kg GBD 0.5 mg/kg ALLO 10 mg/kg GNX20 mg/kg GNX 30 mg/kg LZP 2 mg/kg GBD + ALLO 0.5 mg/kg + 10 mg/kg GBD +GNX 0.5 mg/kg + 20 mg/kg GBD + LZP 0.5 mg/kg + 2 mg/kg  VEH 40% HPβCD

Twenty-four hours prior to administration of the chemoconvulsantpilocarpine, male Sprague Dawley rats (n=13 time or treatment/group;100-125 g at arrival from Charles River Laboratories) will be treatedsystemically with lithium chloride (127 mg/kg; i.p.). On the next day,the rats will receive pilocarpine hydrochloride (50 mg/kg; i.p.) andmonitored carefully for the presence or absence of convulsive seizureactivity. Administration of pilocarpine induces behavioral seizureswithin 5-20 min and any rat not showing convulsive seizure activitywithin 45 min of pilocarpine administration will be excluded fromfurther study. On the study day, the ability of each of theinvestigational compounds (allopregnanolone, ganaxolone, or gaboxadol)or vehicle (VEH) to halt convulsive status epilepticus in the Li-Pilomodel of status epilepticus will be evaluated as outlined in Table 3with administration 30 min after the first observed convulsive seizure.Throughout the study, the experimenter conducting the behavioralobservations will be blinded to treatment conditions (e.g.,allopregnanolone, ganaxolone, or gaboxadol, lorazepam, or VEH). All ratswill be observed and scored for seizure severity for 120 min post drugadministration, and any accompanying behavioral effects will also benoted by an experimenter blinded to treatment conditions. At theconclusion of the behavioral observation period, a 3 mL injection oflactated Ringer's solution will be administered to all surviving rats toreplace any status epilepticus-induced fluid loss.

The dose of each of the investigational compounds will be administeredto rats (n=13/compound dose; Table 3), for a total of 130 rats. A 15%non-responder rate is anticipated for rats pre-treated with Li—Cl, butthat do not develop convulsive status epilepticus in the 45-minute timeperiod. Thus, up to 150 rats will be used for this study, which includespotential non-responders. All animals in the study will be retained for24 hours following completion of the study for assessment of weightchange, as well as overall behavioral appearance at that time (e.g.lethargic/active). Behavioral appearance will be assessed by aninvestigator blinded to treatment condition.

Pharmacokinetics Sample Collection: Brains and plasma will be collectedfor assessment from a cohort of rats for each dose (n=3rats/dose/compound). Plasma will be isolated from trunk blood after10,000×g centrifugation for 10 min at 4° C. The anticoagulant will belithium-heparin. Brains would be snap frozen on dry ice. The testingprocedure timeline is set forth on FIG. 7.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments described herein. Such equivalents are intended to beencompassed by the claims.

1-5. (canceled)
 6. A method of treating CDKL5 disorder comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising ganaxolone or a pharmaceutically acceptable salt thereofwherein the patient is administered up to 1,800 mg of ganaxolone perday.
 7. The method of claim 6, wherein the patient is administeredganaxolone twice daily.
 8. The method of claim 6, wherein thepharmaceutical composition is an oral capsule.
 9. The method of claim 6,wherein the pharmaceutical composition is an oral suspension.
 10. Themethod of claim 6, wherein the pharmaceutical composition comprises 200mg ganaxolone.
 11. The method of claim 6, wherein the pharmaceuticalcomposition comprises 400 mg ganaxolone.
 12. The method of claim 6,wherein the pharmaceutical composition comprises 450 mg ganaxolone. 13.The method of claim 6, wherein the pharmaceutical composition comprises600 mg ganaxolone.
 14. The method of claim 6, wherein the pharmaceuticalcomposition comprises 900 mg ganaxolone.
 15. The method of claim 6,wherein the pharmaceutical composition comprises 1800 mg ganaxolone. 16.The method of claim 6, wherein the patient is administered oral capsulescomprising 200-600 mg ganaxolone twice daily.
 17. The method of claim 6,wherein the composition provides reduction in the frequency of seizures.18. The method of claim 6, wherein the composition provides reduction inthe frequency of seizures, the severity of seizures, or a combinationthereof.